PL187712B1 - Complex compounds of a cascade polymer, method of obtaining them and pharmaceutic agents containing such compounds - Google Patents

Abstract

1 Complex compounds of a cascade polymer, containing a) complexing ligands of the general formula I A-{X-[Y-(Z- (W-Kw z) y ] x} , (I), wherein A as a nitrogen-bearing cascade core of the basic multiplicity a denotes a nitrogen atom, groups of the formulas in which m denotes a number 1-3, n denotes a number 1-3, p denotes a number 0-3, U1 denotes Q1 or E, U2 denotes Q2 or E. and E is a group where o denotes a number 1, Q1 denotes a hydrogen atom or Q2 , and Q2 denotes a direct bond, further M denotes a group - CH2 -, -CO- or -CH2CO-, R° denotes a group -CH2 NU U2, CHi- or NO2, wherein the amount of O2 corresponds to the basic multiplicity, and X and Y independently of each other denote a direct bond or X 1 Y as a reproductive cascade unit of reproductive multiplex x or y and Z 1 W as a reproductive cascade unit of reproductive multiplex z or w denote independently of each other -CH2CH2NH-, -CH2 CH2 N<, -COCH(NH-)(CH2 )4NH-, -COCH(N<)(CH2 )4N<, -COCH2 OCH2CON(CH2CH2NH-)2, -COCH2 OCH2CON(CH2CH2 N<)2, -COCH2 N(CH2 CH2 NH-2, -COCH2 N(CH2CH2 N<)2, -c o c h 2 n h -, -c o c h 2 n <, -COCH2 CH2 CON(CH2 CH2 NH-)2, -COCH2 CH2 CON(CH2 CH2N<)2, -COCHzOCFfcCONH-Ort-CHtCHjCONCaizCHjNH-fch, -C O C H 20C H 2 C O N H -Q H 4 -C H [C H ^X )N (C H ^rH 2N < )2l2 , -C O C H jC H jC O -N H ^ L r C H fC H jC O N C C H jC H a N H -M ,, . . . PL PL PL PL

Description

The invention relates to new cascade polymer complex compounds, pharmaceutical compositions containing them and the use of these complex compounds for the production of diagnostic agents.

Currently, clinically used contrast agents for modern imaging methods of nuclear spin tomography (MRI) and computed tomography (CT) [Magnevist®, Pro Hance®, Ultravist® and Omniscan®] diffuse throughout the extracellular space of the body (intravascular space and parenchyma). This scattering space covers approximately 20% of the body's volume.

Clinical extracellular MRI contrast agents were first used successfully in the diagnosis of cerebral and spinal disease processes, as here a quite specific situation emerges with respect to the regional scattering space. In the brain and in the spinal cord, extracellular contrast agents in healthy tissue cannot leave the intravascular space due to the blood-brain barrier. In the case of disease processes with disruptions of the blood-brain tissue barrier (e.g. malignant tumors, inflammations, demyelinating diseases, etc.), regions with increased permeability (permeability) of blood vessels for these extracellular contrast agents (Schmiedl et al., MRI of blood- brain barrier permeability in astrocytic gliomas: application of small and larg molecular weight contrast media, Magn. Reson. Med. 22: 288, 1991). By taking advantage of these disturbances in vascular permeability, diseased tissue can be recognized in high contrast against healthy tissue.

Apart from the brain and spinal cord, there is indeed no such permeability barrier for the above-mentioned contrast agents (Canty et al., First-pass entry of nonionic contrast agent into the myocardial extravascular space. Effects on rediographic estimate of transit time and blood volume. Circulation 84: 2071) , 1991). Thus, the accumulation of the contrast agent is no longer dependent on the permeability of the vessels, but only on the size of the extracellular space in the respective tissue. The demarcation of these vessels in relation to the surrounding interstitial space is not possible with these contrast agents.

In particular, for the representation of the vessels, a contrast agent that disperses exclusively in the vascular space (vessel space) would be recommended. Such a blood-pool center should enable the separation of well-supplied tissue from poorly supplied tissue by means of nuclear spin tomography, and thus the diagnosis of ischemia. Also, the infarct tissue, due to its anemia, allows itself to be demarcated from the surrounding healthy or ischemic tissue when a vascular contrast medium is used. This is of particular importance when it comes to, for example, distinguishing a heart attack from ischemia.

To date, most patients with suspected cardiovascular disease (the disease is the most common cause of death in industrialized Western countries) must undergo invasive diagnostic tests. In angiography, X-ray diagnostics using iodine-based contrast agents are currently used. These studies are associated with various disadvantages: they are related to the risk of radiation burden and to the discomforts and burdens that arise from this, as compared to NMR-contrast agents, iodine-based contrast agents must be used at a much higher concentration.

187 712

There is therefore a need for NMR contrast agents that can mark the vascular space (blood-pool agents). These compounds should be distinguished by good agreement and high activity (high signal intensity increase in MRI).

The disposition to solve at least some of these problems by the use of macromolecular or macromolecular complexing agents has so far been successful with only very limited success.

Thus, for example, the number of paramagnetic centers in complex compounds, which are described in European patent applications No. 0 088 695 and No. 0 150 844, is not sufficient for a satisfactory visual display.

If the amount of metal ions needed is increased by repeatedly introducing complexing units into the macromolecular biomolecule, it is associated with an intolerable loss of affinity and / or specificity of this biomolecule [J. Humming. Med. 24, 1158 (1983)].

Macromolecules are generally suitable as a contrast agent for angiography. Albumin-Gd-DTPA (Radiology 1987; 162: 205), for example, shows an accumulation in the hepatic tissue of almost 30% of the dose 24 hours after intravenous injection in rats. In addition, only 20% of the dose is eliminated within 24 hours.

The macromolecule polylysine-GdDTPA (European Patent Application Publication No. 0 233 619 also proved to be suitable as a blood-pool-agent. However, this compound consists of a production-mediated mixture of molecules of varying size. In excretion trials in rats, it is possible to It has been shown that this macromolecule is excreted unchanged by renal glomerular filtration, but polylysine-GdDTPA may also contain synthesized macromolecules which are so large that they cannot pass through kidney capillaries in the event of glomerular filtration and thus remain in the body.

Also already described (European Patent Application, Publication No. 0 326 226) macromolecular contrast agents based on carbohydrates. A disadvantage of these compounds is that they generally only transmit about 5% of the signal-enhancing paramagnetic cation.

The polymers described in European Patent Application 0 430 863 and in German Laid-Open DE 43 44 460 are already a step on the way to blood pool agents, since they no longer exhibit the size and molecular weight heterogeneity characteristic of the aforementioned polymers. . However, as well as the compounds disclosed by Wienef et al. In Magnetic Resonance in Medicme, January 1994 (pages 1-8), they still leave much to be desired in terms of total expulsion, compatibility and / or efficacy.

There was therefore a task to provide new diagnostic means, primarily for the diagnosis and localization of vascular diseases, which would not have the disadvantages discussed. This task is solved by the present invention.

It has been found that complex compounds that consist of nitriding, complex-forming ligands of cascade polymers, with at least 16 element ions having an ordinal number of 20-29, 39, 42, 44 or 57-83 and possibly cations of inorganic bases and / or organic, amino acids or amino acid amides, and containing optionally acylated amino groups, are surprisingly well suited for the preparation of NMR-diagnostic and X-ray diagnostic agents without having the disadvantages discussed.

New to the invention are cascade polymer complex compounds containing

a) Complex-forming ligands of general formula I

A- {X- [Y- (Z- (WK _W ) _Z ) y] _x } a (I),

187 712 in which

A as the nitriding cascade core of the basic multiple of a represents a nitrogen atom, groups with the formulas

N-CH ₂ (CH ₂ ) _m U '

N - CH ₂ - (CH ₂ ) _n --N

U ¹

U ¹ uN-CH, -CH, -N

CH.

CH.

(CH ₂ ) (CH ₂ )

N -) - CH ₉ - CH ₉ N

U ² ^ u ²

AT'

U ', CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ Ń — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N

AT'

AT'

CH ₂ CH ₂ —N — CH ₂ CH ₂ —H — CH ₂ CH {

l) 'u24

187 712

,AT

R ° C (M—

V

where m is 1-3, n is 1-3, p is 0-3, U ¹ is Q * or E,

187 712

U ² is q2 or E and E is a group

Q '/

- (CH ₂ ) _O -CH ₂ -N \

Q ² where o is the number 1,

Q [is hydrogen or Q2, and q2 is a direct bond, further M is -CH ₂ -, -CO- or -CH ₂ CO-,

R ° represents the group -CHENU ¹ ! ©, CH3- or NO2, the amount of Q ² being the fundamental multiple of a,

X and Y independently of each other denote direct bond or X and Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w denote independently of each other

-CH2CH2NH-; -CH ₂ CH ₂ N <;

-CNCH (NH -) (CH2) 4NH-; -COCH (N <) (CH 2) 4N <;

-CNCH2NCHoCNN (CH2CH2NH-) ,; -COCH ₂ OCH ^^ (ON (CH ₂ CH ₂ N <) 2; -COCH ₂ N (CH ₂ OH ₂ NH-) 2; -COCH ₂ CH ₂ CH ₂ H;

-COCH ₂ NH-; -COCH2N <;

-CNCH ₂ CH ₂ CNN (CH2CH2NH-) ₂ ; CNN -CNOH2CH ₂ (CH 2 CH ^^ <) _2;

-CNCH ₂ NCH ₂ CONH-C6H4-CH [CH ₂ CNN (CH ₂ CH2NH-) ₂ ] 2;

-CNCH2NCH ₂ CONH-C6H4-CH [CH2CNN (CH ₂ CH ₂ N <) ₂ ] 2;

-CNCH2CH CN _2-NH-C6 H4 -CH [CH2CNN (CH 2 CH ₂ NH-) _2] 2;

-CNCH ₂ CH ₂ CN-NH-C6H4-CH [CH2CNN (CH2CH2N &lt;) ₂ ] ₂ ;

-CNNH-C6H4-CH [CH ₂ CNN (CH ₂ CH ₂ NH-) ₂ ] 2;

-CONH-C6H4-CH [CH2CON (OH ₂ CH ₂ N <) 2] 2;

-CNCH (NH-) CH (CNNH) NH-; -CNCH (N <) OH (CNNH) N <; groups of formula

CON (CH ₂ CH ₂ N <) ₂

187 712

-CONH ·

-CONH \\

CON (CH ₂ CH ₂ NH-) ₂

CON (CH ₂ CH ₂ NH-) ₂

CON (CH ₂ CH ₂ N <) ₂

OCH ₂ CH ₂ NHoch ₂ ch ₂ n <

187 712

O (a-kCH ₂ O) CH ₂ CH ₂ NH- IO (Ch ^ CH ₂ O) Cl ^ CH ₂ N <

K is the radical of the Pcmele factor, and is the number 2-12, x, y, z and, independently of each other, represent the number 1-4, provided that at least two reproductive units are different and that for the product of the multiple there is a relationship

16 <axyzw <64,

b) at least 16 element ions with the order number 20-29, 39, 42, 44 or 57-83,

c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and

d) optionally acylated terminal amino groups, characterized by the following features with a terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the PcmplyP-forming factor K is a radical of the general formula IA

R ¹ OOC-R ² HC _r 3

N-CH ₂ - CH ₂ -N ch ₂ ch ₉

II ² ch ₂ ch ₉

I and

N-CH ₉ - CH ₉ -N /

CHR ² -COOR ¹ CHR ² -COOR ¹ (IA) where

R ^1, independently of each other, represent a hydrogen atom or an equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83,

R2 represents a hydrogen atom, a methyl or ethyl radical which is optionally substituted with 1-2 hydroxyl groups or 1 carboxyl group,

R ³ is a group

R ² R ⁴

I and

-ch-co-nu ⁶ -t

R4 is a straight chain, branched, saturated or unsaturated C1-C3alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 Cenylene group, 1 Tinylene Psyl group, and / or optionally substituted with 1-5 hydroxyl groups, 1-3 carboxyl groups, 1 phenyl group,

U6 is a C 1-8 alkylene chain, containing -CH2-, -CH2NHCO-, -NHCOCH2O-, -NHCOCH2OC6H4-, -N (CH2CO2H) -, -NHCOdH2d6H4-, -NHCsN ^^ -, -CH2OC6H4-, -CH2CH2O groups - and / or substituted with -COOH, -CH2COOH groups, preferably

187 712 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -C6H4-, -C6Hi0-, -CH2C6H5-, _-CH2 NHCOCH2CH (CH 2 CO ₂ H) -C6H4-, _-CH2 nhcoch _{2 OCH2} -, -ch ₂ nhcoch2c6H4-,

T represents the group -CO-a, -NHCO-a or -NHCS-a, and a represents the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W.

A preferred new compound according to the invention is a 24-mer Gd-N- (5-DO3A-yl-4-keto-3-azacaprooyl) -polyamide complex cascaded on the basis of N, N, N ^z , N ', N, N-six Trimazinic acid [2- (trisylamino) ethyl] -trimamide.

The pharmaceutical composition containing additives customary in galenic pharmacy and the active ingredient is distinguished according to the invention by the fact that it contains as active ingredient a cascade polymer complex compound containing

a) Complex-forming ligands of general formula I

A- {X- [Y- (Z- (WK _w ) _z ) _y ] _x } _a (D, where

A as the nitriding cascade core of the basic multiple of a represents a nitrogen atom, groups with the formulas

U ¹

U ¹

N-CH ₂ (CH ₂ )

N — CH ₂ - (CH ₂ ) _n —N uU '

U ¹

N-CHo —CH ₂ Φ ^{2 2}

CH, (CH ₂ )

U ^from N

CH ₂

I <θ ^Μ 2> πι

- sl

U ²

U 'u

AND

CH ₂ CH 2 — N — CH ₂ CH ₂ —N — CH ₂ CH ₂ ^X u ² [sl — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N

AT'

AT'

CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂

U 'u187 712

<

N \ and where m is 1-3, n is 1-3, p is 0-3, U ¹ is Q ¹ or E,

187 712

U2 is Q2 or E and E is a group

Ω ¹ /

- (CH ₂ ) _o -CH ₂ -N \

Q ² where o is the number 1, ^u 9

Q is hydrogen or Q, and Q ² represents a direct bond, hereinafter M is -CH2-, -CO- or -CH 2 CO-,

R ° represents the group -CH ₂ NU'U ² , CH3- or NO2, the amount of Q ² being the fundamental multiple of a,

X and Y independently of each other denote direct bond either X and Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w denote independently of each other

-CH ₂ CH2NH-; -CH ₂ CH ₂ N <;

-COCH (NH -) (CH2) 4NH-; -COCH (N <) (CH ₂₎ 4 N <;

-COCH2OCH ₂ CON (CH ₂ CH2NH-) ₂ ; -COCH2OCH ₂ CON (CH ₂ CH2N &lt;)2; -COCH ₂ N (CH ₂ CH ₂ NH-) 2; -COCH2N (CH2CH2N <) 2;

-COCH2NH-; -COCH ₂ N <;

-COCH ₂ CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ N <) 2;

-COCH2OCH ₂ CONH-C ₆ H ^^ <^^ [CH2CON _(CH2 CH2NH-) 2] 2;

-COCH ₂ OCH ₂ CONH-C6H4-CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ^^^^ [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] 2;

-COCH ₂ CH ₂ CO-NH-C ₆ n4 -CH [CH. ₂ CON (CH ₂ CH ₂ N <) ₂ ] 2;

-CONH-C6H4-CH [CH2CON (CH 2 CH ₂ NH-) 2] 2 ·;

-CONH-C6H4-CH [CH2CON (CH 2 CH ₂ N <) 2] 2;

-COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <; groups of formula

CON (CH ₂ CH ₂ N <) ₂

187 712

-CONH

-CONH \\

CON (CH ₂ CH ₂ NH-) ₂

CON (CH ₂ CH ₂ NH-) ₂

CON (CH ₂ CH ₂ N <) ₂

CON (CH ₂ CH ₂ N <) ₂

187 712

K denotes the radical of the complexing agent, a denotes the number 2 -12, x, y, z, and independently represent the number 1-4, provided that at least two reproductive units are different and that the relationship <a -xy - z - w <64,

b) at least 16 element ions with the ordinal number 20-29, 39, 42, 44 or 57-83,

c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and

d) amino terminal amino groups cited, if any, characterized by the following:

with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K is a radical of the general formula LA

R ¹ OOC-R ² HC r3

N-CH ₂ - CH ₂ -N

CH ₂ ch ₉

II ²

CH ₂ ch ₂

-CH ₂ - CH ₂ CHR ² -COOR ¹ CHR ² -COOR ¹ (IA) where

R ^1, independently of each other, represent a hydrogen atom or an equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83,

R2 represents a hydrogen atom, a methyl or ethyl radical which is optionally substituted with 1-2 hydroxyl groups or 1 carboxyl group,

R ³ is a group

R ² R ⁴

I and

-CH-CO-NU ⁶ -T r4 represents a straight chain, branched, saturated or unsaturated C1-Cbo-alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 phenylene group, 1 phenylene-N-xyl group and / or optionally substituted 1-5 hydroxyl groups, 1-3 carboxyl groups, 1 phenyl group,

U is a Ci-Cca-alkylene chain containing -CH2-, -CH2NHCO-, -NHCOCH2O-, -NHCOCH2OC6H4-, -N (CH2CO2H) -, -NHCOCH ^ C6H4, -NHCSNHC ₆ H4-, -CH2OC6H4- groups, -CH2CH2O- and / or substituted by -COOH, -CH 2 COOH, preferably a group -CH2-, -CH2CH2-, -CH2CH2CH2-, -OH ^ -CgHio-, -CH2C6H5-, -CH2NHCOCH2CH (CH ₂ CO 2 H) -C ₆ H4-, -CH2NHCOCH2OCH2-, -CH2NHCOCH2C6H4-,

T represents the group -CO-α, -NHCO-a or -NHCS-a, and a represents the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W.

The invention further relates to the use of a cascade polymer complex compound containing

a) Complex-forming ligands of general formula I

A- {X- [Y- (Z- <WK _w > ₂ ) _y ] _x } _a (I),

Wherein as the nitriding cascade core of the basic multiple of a is a nitrogen atom, groups of the formulas

U ¹

CH ₂ (CH ₂ ) _m

U ²

AT'

NΦ

CH,

I (CH ₂ )

AT'

N - CH ₂ (CH ₂ ) _n N

U '• ch ₂ —ch ₂ n - ^ - ch ₉ -ch ₉ 2 / p

U ^with -N

CH ₉

I (= ^h 2) m

-N \ 2 'U ²

AT'

AT'

CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ , ^X u ²

N— CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N uU '

CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ u-

187 712

U ¹

R ° C (M-N \ 2/3

where m is 1-3, n is 1-3, p is 0-3,

U ¹ is O ¹ or E,

U is Q or E and E is a group

Q '/

- (CH ₂ ) _O -CH ₂ -N \

Q ² where o is the number 1,

Q 'is hydrogen or Q ² , and Q ² is a direct bond, further M is -CH ₂ -, -CO- or -CH ₂ CO-,

R ° represents the group -CH ¹ NU ¹ !} ² , CH 3 - or NO ₂ , the amount of Q ² being the fundamental multiple of a,

X and Y independently of each other denote direct bond either X and Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w denote independently of each other

187 712

-CH2OH2NH-; -ch ₂ ch ₂ n <;

-COOH (NH -) (OH2) 4NH-; -OOOH (N <) (CH2) 4N <;

-COCH2OCH2OON (OH2CH2NH-) 2; -COCH2OOH2ONN (CH2OH2N <)2; -COCH2N (OH2OH2NH-) 2; -COCH2N (CH2CH2N <) 2;

-COOH2NH-; -OOOH2N <;

-COOH2OH2CON (OH2OH2NH-) 2; -COCH2CH2ONN (CH2OH2N <)2;

-OOCH2OCH2OONH-O6H4-OH [OH2OON (CH 2 CH ₂ NH-) 2] 2;

-COOH2OCH ₂ OONH-O6H4-CH [CH ₂ CNN (CH ₂ CH ₂ N 6) 2] 2;

-OOCH ₂ OH ₂ CO-NH-C 6 H 4 - 4 CH [CH ₂ CON (CH ₂ CH ₂ NH-) 2.12;

-coch ₂ oh ₂ CO-nh-c ₆ b ₁₄ H 2: 'h [ch ₂ con (Ch ₂ CH ₂ n <) 2] 2;

-CONH-C6H4-CH [CH ₂ -CON (cH2CH2Nh-) 2] 2;

-CONH-O6H4-CH [CH ₂ CON (OH ₂ OH ₂ N <) ₂ ] ₂ ;

-COOH (NH-) OH (OOOH) NH-; -COCH (N <) CH (OOOH) N <;

groups of formula

con (ch ₂ ch ₂ n <) ₂

187 712

K denotes the radical of the complexing agent, a denotes the number 2-12, x, y, z and independently represent the number 1-4, provided that at least two reproductive units are different and that the relationship <ax y z w <64,

b) at least 16 element ions with the order number 20-29, 39, 42, 44 or 57-83,

c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and

(d) optionally acylated amino terminal groups, characterized by the following features:

with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K is a radical of the general formula LA

R ¹ OOC-R ² HC r3

N-CH ₂ - CH ₂ -N

CH, CH,! and ch ₂ ch ₂

N-CH, -CH, -N

X ^{2 2} \

CHR ² -COOR ¹ CHR ² -COOR ¹ (IA),

187 712 in which

R1 are independently of each other a hydrogen atom or the equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83,

R ² is hydrogen, methyl or ethyl, which is optionally substituted by 1-2 hydroxyl or 1 carboxy group,

R ³ is a group

R ² R ⁴

I and

-ch-co-nu ⁶ -t,

R ⁴ is a straight chain, branched, saturated or unsaturated C 1 -C 6 alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 phenylene group, 1 phenyleneoxy group and / or optionally substituted with 1-5 hydroxyl groups, 1-3 carboxyl groups 1 phenyl group

U ⁶ is a C 1 -C 20 -alkylene chain containing -CH ₂ -, -CH ₂ NHCO-, -NHCOCH ₂ O-, -NHCOCH2OC6H4-, -N (CH ₂ CC> 2H) -, -NHCOCH2C6H4-, -NHCSNHC groups ₆ H4-, -CH2OC6H4-, -CH2CH20- and / or substituted by -COOH, -CH2COOH groups, preferably is -CH2-, -CH2CH2-, -CH2CH2CH2-, -C6H4-, -CeHio-, -CH2C6H5-, - CH2NHC0CH2CH (CH2C02H) -CeH4-, -CH2NHCOCH2OCH2-, -CH ₂ NHCOCH2C ₆ H4-,

T represents the group -CO-α, -NHCO-a or -NHCS-a, aa represents the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W, for the production of agents for NMR diagnostics or for X-ray diagnostics, especially conventional methods and computed tomography .

Another object of the invention is the use of a cascade polymer complex compound containing

a) Complex-forming ligands of general formula I

A- {X- [Y- (Z- (WK _w ) _z ) _y ] _x } _a (I), where

A as the nitriding cascade core of the basic multiple of a represents a nitrogen atom, groups with the formulas

U ¹

N-CH ₂ (CH ₂ )

N— CH.

(CH ₂ ) _n

ch ₂ ch ₂

Z \ | \

u ¹

U '^ ^H 2) m (CH ₂ ) m

CH, - CH, -N / Z n ^{2 2} \ "

U ² ^ ^P u2

187 712

CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂

N— CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N

CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ '

\ 2

R ° C (M — N

187,712 where m is 1-3, n is 1-3, p is 0-3,

U ¹ is Q * or E,

U ² is Q ² or E and E is a group

Ω ¹ /

- (CH2) _o -CH ₂ -N \

Ω ² where o is the number 1,

Ω ¹ represents a hydrogen atom or Ω ² »and Ω ² represents a direct bond, further M represents a -CH ₂ -, -CO- or -CH ₂ CO- group,

R ° is a group -CHsNU ^ ^2, CH ₃ - or NO _2, wherein the amount of O ² corresponds to the base multiplicity a,

X and Y independently of each other denote direct bond either X and Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w denote independently of each other

-CH ₂ CH ₂ NH-; -CH ₂ CH ₂ N <;

-ΩΩΩΗ (ΝΗ -) (ΩΗ ₂ ) ₄ ΝΗ-; -COCH (N <) (CH ₂ ) ₄ N <;

-COCH ₂ OCH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ OCH ₂ CON (CH ₂ CH ₂ N <) ₂ ; -COCH ₂ N (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ N (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ NH-; -COCH ₂ N <;

-COCH ₂ CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCI1 ₂ CH ₂ CON (CH ₂ CH ₂ N <) ₂ ;

-COCH 2 CH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-COCH ₂ OCH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N 6) ₂ ] ₂ ;

-ΩΩΝΗ-α ₆ Η ₄ -αΗ [ΩΗ ₂ ΩΟΝ (ΩΗ ₂ ΩΗ ₂ ΝΗ-) ₂ ] 2;

-CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <; groups of formula

CON (CH ₂ CH ₂ NH-) ₂

-coch ₂ oh ₂ coni

CON (CH ₂ CH ₂ NH-) ₂

CON (CH ₂ CH ₂ N <) ₂

187 712

CON (CH ₂ CH ₂ N <) ₂ -coch ₂ ch ₂ conh-C y

CON (CH ₂ CH ₂ N <) ₂

O (CH 2 CH ₂ O) Cl-kCH2NHO (C H CH ₂ O) CH ₂ CI ^ NH-

O (C1 ^ CH ₂ O) CH 2 CH ₂ N

O (CH ₂ CH ₂ O) Cl 2 CH ₂ N <

O (CH2CH ₂ O) CH2CH ₂ NHO (Cl- ^ CH ₂ O) Cl- ^ CH ₂ N <

187 712

K denotes the radical of the complexing agent, a denotes the number 2-12, x, y, z and independently represent the number 1-4, provided that at least two reproductive units are different and that the relationship <a x yw <64,

b) at least 16 element ions with the order number 20-29, 39, 42, 44 or 57-83,

c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and

(d) optionally acylated amino terminal groups, characterized by the following features:

with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K is a radical of the general formula IA

R ¹ OOC-R ² HC r3

N-CH ₂ - CH ₂ -N

CH, CH, i ² ch ₂ ch ^{_2/2 2} \ ² Chr ¹ Chr ² COOR COOR ¹ (IA), wherein

R1 are independently of each other a hydrogen atom or the equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83,

R ² is hydrogen, methyl or ethyl, which is optionally substituted by 1-2 hydroxyl or 1 carboxy group,

R3 is a group

R ² R ⁴

I and

-ch-co-nu ⁶ -t, R 4 is a straight chain, branched, saturated or unsaturated C 1 -C 6 -alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 phenylene group, 1 phenyleneoxy group and / or optionally substituted with 1 -5 hydroxyl groups, 1-3 carboxyl groups, 1 phenyl group,

U ⁶ is a C 1 -C 20 -alkylene chain containing -CH ₂ -, -CH ₂ NHCO-, -NHCOCH ₂ O-, -NHCOCH2OC ₆ H4-, -N (CH2CO2H) - groups, -NHCOCH ₂ C ₆ H4-, -NHCSNHCeH,; -, -CH 2 OC6H4-, -CH2CH 2 O- and / or substituted by -COOH, -CH2 COOH groups, preferably is -CH 2-, -CH 2 CH ₂ -, -CH2 CH 2 Ch 2 -, -C6Hi 4-, -C6Hio-, -CH 2CeH 5-,

-CH ₂ NHCOCH2CH (CH ₂ CO ₂ H) -C6H4-, -CH2NHCOCH ₂ OCH ₂ -, -CH ₂ NHCOCH2C6H4-,

T AA7n / -rr (jnino IpK. MUPC.rt a

OZAiciC-it · Hi Lime OL lUS 1 w. ₅ u.

a represents the binding site at the terminal nitrogen atom of the last generation reproductive unit W, for producing agents for distinguishing between benign and malignant tumors in regions of the body without the blood-brain tissue barrier.

If the agent of the invention is to be used in NMR diagnostics, the central ion of the complex salt must be paramagnetic. These are especially the two-1 trivalent ions of the elements of the order numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, chromium (HI), iron (II), cobalt (II), nickel (II), copper (II), prase42

187 712 of odymium (IH), neodymium (IH), samarium (III) and ytterbium (III). Due to their very strong magnetic moment, gadolinium (III), terbium (IH), dysprosium (HI), holmium (III), erbium (IH), manganese (II) and iron (III) ions are particularly preferred.

If the agent of the invention is to be used in X-ray diagnostics, then the central ion must be derived from an element with a higher ordinal number to obtain sufficient absorption of X-rays. Diagnostic agents which contain a physiologically acceptable complex salt with the central element ions having an ordinal number of 21-29, 39, 42, 44, 57-83 have been found suitable for this purpose; this is for example the lanthanum (HI) ion and the above-mentioned ions from the lanthanide series.

The cascade polymer complex compounds according to the invention contain at least 16 element ions of the above-mentioned ordinal number.

The remaining acidic hydrogen atoms, i.e. those atoms which have not been substituted by the central ion, may optionally be replaced wholly or partially with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Suitable inorganic cations include lithium ion, potassium ion, calcium ion, magnesium ion, and especially sodium ion. Suitable cations of organic bases include, but are not limited to, cations of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine, especially N-methylglucamine. Suitable amino acid cations are, for example, the cations of lysine, arginine and omithin and amides of otherwise acidic or neutral amino acids.

The compounds according to the invention having a molecular weight of 10,000-80,000 D, preferably 15,000-40,000 D, exhibit the desired properties as discussed in the introduction. They contain a large number of metal ions, which are permanently bound in a complex compound, necessary for their use.

They accumulate in areas of increased vascular permeability, e.g. in tumors, allow for a judgment on tissue perfusion, enable the determination of blood volume in tissues, selectively reduce relaxation times or blood density, and graphically represent the permeability of blood vessels. Such physiological information cannot be obtained with the use of extracellular contrast agents such as Gd-DTPA [Magnevist®]. From this point of view, in the case of modern visionary methods of nuclear spin tomography and computed tomography, areas of application also emerge: species diagnosis of malignant tumors, early treatment control in the case of cytostatic, anti-inflammatory or vasodilator treatment, early diagnosis of areas with reduced perfusion (e.g. in the muscle cardiac disease), angiography in vascular diseases, and the diagnosis and diagnosis of inflammations (sterile and infectious).

The cascade polymer complex compounds according to the invention are also excellently suited for (interstitial and intravenous) lymphography.

As a further advantage over extracellular contrast agents such as Gd-DTPA [Magnevist®j, it must be emphasized that it is more effective as a contrast agent for nuclear spin tomography (higher relaxation), which leads to a marked reduction in the diagnostic dose. At the same time, the contrast agents according to the invention can be prepared as solutions iso-osmolally with respect to the blood, and thus reduce the osmotic load on the body, which is expressed in the reduced toxicity of this substance (higher toxic threshold). Lower doses and a higher toxic threshold lead to a marked increase in the safety of using a contrast agent in modern vision methods.

Compared to macromolecular contrast agents based on carbohydrates, e.g. dextran (European Patent Application, Publication No. 0 326 226), which - as already mentioned - generally only carry about 5% of the paramagnetic signal-enhancing cation, the polymer complexes according to the invention have a content of as a rule, about 20% of the paramagnetic cation. Thus, the macromolecules according to the invention in relation to the molecule cause a much higher signal amplification, which at the same time leads to the fact that compared to macromolecular contrast agents

187 712 based on carbohydrates, the dose required for nuclear spin tomography is much lower.

By means of the polymer complexes according to the invention, it has been possible to construct and produce macromolecules that have a uniformly defined molecular weight. Thus, it is surprisingly possible to control the size of these macromolecules so that they are large enough to only slowly leave the vascular space, but at the same time small enough to pass through kidney capillaries, which are 300-800 L.

Compared to the other mentioned polymeric compounds of the prior art, the cascade polymer complex compounds according to the invention are distinguished by improved excretion capacity, higher efficiency, higher stability and / or better compatibility.

A further advantage of the present invention is that complex compounds with hydrophilic or lipophilic, macrocyclic or open chain, small or high molecular weight ligands have now become available. As a result, the compatibility and pharmacokinetics of these polymer complexes can be controlled by chemical substitution.

The pharmaceutical compositions according to the invention are prepared in a manner which is well known in the art, wherein the complex compounds according to the invention are suspended or dissolved in an aqueous medium with the addition of additives customary in galenic pharmacy, and the suspension or solution is then optionally sterilized. Suitable additives are, for example, physiologically acceptable buffer substances (such as tromethamine), additives of complexing agents or weak complexes (such as e.g. if necessary - antioxidants such as ascorbic acid, for example.

If, for enteral administration or other purposes, suspensions or solutions of the agents of the invention in water or physiological saline are required, they are mixed with one or more of the auxiliary substances customary in galenic pharmacy [e.g. with methylcellulose, lactose, mannitol] and / or with surfactant (s) [e.g. with lecithin, an agent called Tween®, Myrj®] and / or with an anti-tasting agent (s) to improve the taste [e.g. with essential oils].

In principle, it is possible to prepare the pharmaceutical compositions of the invention even without isolating the complex salts. In any case, care must be taken to ensure that the chelate formation is carried out in such a way that the salts and salt solutions according to the invention are practically free of uncomplexed, toxic metal ions.

This can be ensured, for example, by means of color indicators such as xylenol orange by a test titration during the manufacturing process. The purification of the isolated complex salt remains the ultimate guarantee.

The pharmaceutical compositions according to the invention preferably contain 1 μπκ) 1-1.3 mol / liter complex salt and are generally dosed in an amount of 0.0001-5 mmol / kg. They are intended for enteral and parenteral administration. The complex compounds according to the invention are suitable for use:

1. for NMR diagnostics and X-ray diagnostics in the form of its complexes with element ions with the ordinal numbers 21-29, 39,42, 44 and 57-83;

2.for radiodiagnostics and radiotherapy in the form of their complexes with radioisotopes of elements with the ordinal numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 and 77.

The agents according to the invention fulfill the multiple rationale for being suitable as contrast agents for nuclear spin tomography. Thus, they are excellently suited for improving the expressive power of the image obtained with the nuclear spin tomograph by increasing the signal intensity after oral or parenteral administration. Moreover, they show high efficiency, which is necessary to load the system with the lowest possible amounts of foreign substances, and good compatibility, which is necessary to maintain the non-invasive nature of these tests.

187 712

Easy solubility in water and low osmolality of the agents according to the invention allow for the preparation of high concentration solutions in order to keep the volume load on the circulation within the acceptable limits and to compensate for the dilution by the body fluid, i.e. the diagnostic NMR agents must be 100-1000 times more soluble in water than for NMR spectroscopy. Moreover, the agents according to the invention show not only high in vitro stability, but also surprisingly high in vivo stability, so that the release or exchange of non-covalently bound ions in complexes - ions that are actually poisons - during the period in which these new contrast agents are completely excreted. it only happens extremely slowly.

In general, the agents of the invention for use as NMR diagnostic agents are dosed at 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Details of this application are for example discussed by H.-J. Weinmann and colleagues in Am. J. of Roentgenology 142, 619 (1984).

Particularly low dosages (below 1 mg / kg body weight) of organ-specific NMR diagnostic agents are suitable, for example, for the detection of tumors and myocardial infarction.

Moreover, the complex compounds of the invention can advantageously be used as compliance reagents and as shift reagents for in vivo NMR spectroscopy.

Due to their favorable radioactive properties and the good stability of the complex compounds contained therein, the agents according to the invention are suitable as radiodiagnostics. Details of their use and dosage are discussed in, for example, "Radiotracers for Medical Applications, CRC-Press, Boca Raton, Florida.

A further visionary method with radioisotopes is positron emission tomography, which uses positron emitting isotopes such as ⁴³ Sc, ^ Sc, re, ⁵⁵ Co and ^6? Ga (Heiss, WD; ME; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

The compounds of the invention are surprisingly capable of distinguishing between benign and malignant tumors in regions without the blood brain tissue barrier.

They are also distinguished by the fact that they completely remove themselves from the body and are therefore well tolerated.

As the substances according to the invention accumulate in malignant tumors (no diffusion into healthy tissues, but high tumor vascular permeability), they may also support radiotherapy of malignant tumors. This therapy differs from appropriate diagnosis only in the amount and type of isotope used. The aim here is to destroy tumor cells by short-wave ionizing radiation of the shortest possible range. For this purpose, the interaction of metals contained in these complex compounds (such as iron or gadolinium) with ionizing radiation (e.g. with X-rays) or with neutron radiation is used. Due to this effect, the local radiation dose is significantly increased in the place where the metal complex is located (e.g. in tumors). In order to obtain the same radiation dose in the malignant tissue, when using such metal complexes, the radiation load on healthy tissue can be severely reduced and hence side effects burdening the patient is avoided. These metal complex conjugates according to the invention are therefore also suitable as a radiosensitizing substance in the radiotherapy of malignant tumors (e.g. using the Mossbauer effects or in neutron uptake therapy). Suitable β-emitting ions are, for example. 46Sc, ^4? Sc, 4®Sc, ⁷² Ga, ⁷³ Ga and ⁹⁰ Y. Suitable α-emitting ions having low half-lives are, for example, 2 "Bi, ²¹² Bi-Bi and 2 ^M Bi, with 2-Bi being preferred. A suitable photon and electron emitting ion is ¹⁵⁸ Gd, which can be obtained from ^ Gd by neutron capture.

When an agent of the invention is intended for use in a variant of radiotherapy as proposed by RL Mills et al [Nature Vol. 336, (1988). page 787], the central ion must be derived from a MoPbauer isotope, such as e.g. ⁵⁷ Fe or ⁵¹ Eu.

When administered in vivo, the therapeutic agents of the invention may be administered together with a suitable carrier, such as, for example, serum or physiological sodium chloride solution, and together with another protein, such as, for example, human serum albumin.

187 712

The dosage depends on the type of cellular disorder, on the metal ion used and on the type of vision method.

The therapeutic agents of the invention are administered parenterally, preferably intravenously.

Details about radiotherapeutic agents are discussed, for example, by R.W. Kozak et al. WTEBTEC, October 1986, 262.

The agents according to the invention are excellently suitable as X-ray contrast agents, in particular for computed tomography (CT), and it should be particularly emphasized that in biochemical pharmacological studies, no signs of anaphylaxis, known in iodine-containing contrast agents, can be detected in their use. They are especially valuable because of the favorable absorption properties in the range of higher tube voltages for digital differential techniques.

In general, the agents according to the invention for use as X-ray contrast agents are dosed analogously to, for example, Meglumin-Diatrizoat in an amount of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.

Details of the use of X-ray contrast agents are discussed, e.g., by Barke in Rontgenkontrastmittel, G. Thieme, Leipzig (1970) and by P. Thum, E. Buchelef in "Einfuhrung in die Rontgendiagnostik", G. Thieme, Stuttgart, Nowy York (1977).

Summing up, it was possible to synthesize new complexing agents, metal complexes and salts of metal complexes, which open up new possibilities in diagnostic and therapeutic medicine.

The following examples serve to explain the subject matter of the invention in more detail.

Example 1

a) di [2- (benzyloxycarbonylamino) ethyl] amine

51.5 g (500 mmol) of diethylene thyme ii3y m131 mole of triethylthionine is dissolved in dichloromethane, and at -20 ° C, 161 g of benzyl cyanoformate (from Fluka) are added in dichloromethane with the aid of room. After the reaction has ended, it is desiccated in a fume hood, the residue is taken up in diethyl ether, the organic layer is washed with sodium bicarbonate solution and dried with sodium sulfate. The filtrate is mixed with hexane, the precipitate is filtered off and dried.

Yield: 163.4 g (88% of theory).

Elelemntama analysis:

Calcd: C 64.67 H 6.78 Ni 11.11 Found: C 64.58 H 6.83 N 11.28.

b) N, N, N ', N', N, N-six O [[2- (benzyloxycasbonylamino) ethyl] trimosinic acid thymisamide

13.27 g (50 mm0 lim ^ οΜο ^ οι Triennium quauu (from Amyichl and C4.7 ml (250 mmol) of triethylamine are dissolved in V dimethylformamide (DMF) and at 0 ° C add 65.0 g (175 mmoles) of the amine described in Example 1a, then stirred at room temperature overnight The solution is evaporated in vacuo and the residue is chromatographed on silica gel with ethyl acetate.

Yield: 39.4 g (62% of theory).

Elemental analysis:

Calcd: C 65.24 H 5.95 N 9.92 Found: C 65.54 H 5.95 N 9.87.

c) Na, Nj-di-1N, N'-dibenzyloxycasbonyl-11yl) lysine; protected "tri-lysine"

3.6 g (20 mmclO chioIΌwooIWz lysuy iy, 95 ml (50 ηκη0ΐθ trOlethylnmtnz is dissolved in DMF, add 26.8 g (50 mmol) of ρ-aitsophenyl ρ-aitsophenyl esime N ^ N-dubenzyloxycarbonylolysin (from Bachem) and mixed 2 days at room temperature After completion of the reaction, it is evaporated in vacuo, the residue is taken up in ethyl acetate and shaken with dilute hydrochloric acid, the organic layer is dried over sodium sulphate, the solvent is evaporated and the residue is chromatographed with a graded gradient of ethyl acetate / ethanol.

Yield: 10.7 g (57% of theory).

187 712

Elemental Analysis: Calculated: C 63.95 Found: C 63.63

H 6.75 N 8.95

H 6, N 9 N 8.93.

d) Fully protected benzylcPsyParbonyl-24-pollamine based on N, N, N ', N', N, N-hex- [2- (trlysyl-dmino) -ethyl] -trimesinic acid triamide

1.27 g (1 mmeO gześeiobedzolyfbykcpbypyibamine, onisenee in the cephalic acetic acid, is dissolved in glacial acetic acid and mixed with 33% hydrogen bromide in glacial acetic acid with stirring. After 60 minutes with ethyl ether the started precipitation of the amine is complete, the resulting hydrobromide is formed. with diethyl ether, dried in vacuo and used in the reaction discussed below without further purification.

Yield: 0.95 g (quantitative).

7.0 g (7.5 mmoles of trializinyls in human spine, 2 g of 17 mm m-ha) dropsabefzotridzole and 2.4 g (7.5 mmoles) of 2- (1H-benzotriabolyl) tetrafluoroborate l) -1,1,3,3-cbtyromethyluronium (named TBTU; Peboc Limited, UK) is dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethylene diisopropylamin and 0.95 g (1 mmol) of the above-mentioned hexadmin hydrobromide and stirred overnight at room temperature. After the reaction has ended, it is evaporated down in vacuo and the residue is ceromatized with ethyl acetate / ethanol (2: 1) on silica gel.

Yield: 4.55 g (76% of theory).

Elemental analysis:

Calcd: C 64.35 H6.7 L N 10.52 Found C 64.08 H 6.57 N 10.29.

e) 2-Bromopropionylglycine benzyl ester

To 100 g (296.4 mmol) of p-toluenesulfonic acid benzyl glycine ester and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylene chloride are added dropwise at 0 ° C 55.9 g (326.1 mmol) of 2-bromopropionic acid chloride. The temperature is kept at not more than 5 ° C. After the addition was complete, the mixture was stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. 500 ml of ice water are added thereto, and the aqueous layer is adjusted to a pH value of 2 with 10% aqueous hydrochloric acid solution. The organic layer is separated, washed once with 300 ml of 5% aqueous hydrochloric acid each time and 400 ml of water. The organic layer is dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue is tri-crystallized from diisopropyl ether.

Yield: 68.51 g (75% of theory) of a colorless crystalline powder.

Melting point: 69-70 ° C

Elemental analysis:

calcd: C 46.76 H7.19 N 4.54 Br 25.92 Found: C 46.91 H7.28 N 4.45 Br 25.81.

f) 1- [4- (benzyloxycarbonyl) -1-methyl-2-keto-3-dzabutyl] -1,4,7,10-tetraazacyl Plododecane

To 55.8 g (324.4 mmol) of 1,4,7,10-tetraazacyclododecafUi dissolved in 600 ml of chloroform, 50 g (162.2 mmol) of the title compound from Example 1a) are added and the mixture is stirred overnight at room temperature . 500 ml of water are added thereto, the organic layer is separated and washed twice more with 400 ml of water each. The organic layer is dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (circulating medium: chloroform / methanol / 25% aqueous ammonia solution = 10/5/1).

Yield: 40.0 g [63% of theory, with respect to the used compound Ie)] of a slightly yellowish, malleable oil.

187 712

Elemental analysis:

Calcd: C 61.36 H 8.50 N 17.89 Found: C 61.54 H 8.68 N 17.68.

g) sodium bromide complex with 10- [4- (benzyloxykiabonyl) -1-methyl-2-keto-3-azabutyl] -1,4,7-tr- (1H-tert-butok: sycarbo) ] ^^^ i ^ i ^^ '^^) ^ 1,4,7,10-tetrriazacyklodiekanem

33 g (169 mmol) of H1-tert-butyl bromoacetate are added to 20 g (51.08 mmol) of the title compound from Example 1f) and 17.91 g (169 mmol) of sodium carbonate in 300 ml of acetomethyl and the mixture is stirred for 24 hours. hours at 60 ° C. It is cooled to 0 ° C, the salts are filtered off, and the filtrate is concentrated to dryness. The residue is chromatographed on silica gel (circulation agent: ethyl acetate / ethanol = 15/1). The fractions containing the product are evaporated and the residue is recrystallized from diisopropyl ether.

Yield: 34.62 g (81% of theory) of a colorless crystalline powder.

Melting point: 116-117 ° C.

Elemental analysis:

Calcd: C 54.54 H 7.59 N 8.37 Na 2.74 B8 9.56 Found: C 54/70 H 8.5 N 8.24 Na 2.60 338 9.37.

h) Sodium bromide complex compound with 10- (4-k; arboxy-1-methylt2tketot3tasate but ^ -1 ^^ J ^^ i ^ ć) j ^ (En ^ -i ^ .- t ^ u ^ t ^ ok ^ sycarbonylmethyl) -1,4,7,10-tetraazacyclododecane g (35.85 mmol) of the title compound from Example 1g) is dissolved in 500 ml of isopropanol and 3 g of a palladium catalyst (10% Pd / C) are added. This was hydrogenated overnight at room temperature. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo and recrystallized from acetone.

Yield: 22.75 g (85% of theory) of a colorless crystalline powder.

Melting point: 225 ° C (with decomposition).

Elemental analysis:

Calcd: C 84.6 H 8.66 N 9.38 Na 3.07 B8 10.71 Found: C 44.75 H 7.81 N 9.25 Na 2.94 B8 10.58.

i) 24-meric N- (5-DO3A-yl-4-keto-3-azaaaprollo) -polyamide N, N, N ', N', N, N-six- [2t (TrlysylammoJ-ethyl] -trimazinic acid

6.0 g (1 mmol) of the ^ benzyloNsykarbonyloamina they ^are aoej an p8zykłrdzie dd), dissolved in glacial acetic acid and mixed with 33% towego hydrogen bromide in glacial acetic acid. After 3 hours, the precipitation which has begun is complete with diethyl ether, the resulting 24-amine hydrobromide is washed with diethyl ether and dried in a vacuum.

35.84 g (48 mmoles) of the acid described in the previous example 1h), dissolved in DMF, are treated with: 7.35 g (48 mmoles) 1-hzdIΌksybenzsstπadoiu, 15.41 g (48 mmoles) TBTU (from Peboc Limited, UK) and 49.3 ml (288 mmol) of Ntetzlodisoprot pylamine and stirred for 20 minutes at room temperature. This solution is then mixed with the above-described (1 mmol) 24-amine hydrobromide and stirred for 4 days at room temperature. This solution is concentrated in vacuo, the residual oil is cooled in an ice bath and treated with trifluoroacetic acid, stirred overnight at room temperature, then precipitated with diethyl ether. The precipitate is dried in vacuo, taken up in water, adjusted to a pH value of 7, cleaned of low molecular weight components on an AMICON® YM3 ultrafiltration membrane, and the retentate finally subjected to membrane filtration and lyophilization.

Yield: 13.5 g (83% of theory).

Water content (Karl-Fischer). 6.2%.

Elemental analysis (referenced to the anhydrous substance): Calculated: C 45.82 H 6.09 N 15.07 Na 10.79 Found: C 45.56 H 6.15 N 1/16/2 (0 Na 10.52.,

187 712

In the title compound li) the abbreviation DO3A stands for 1,4,7-tr- (carboxymethyl) -1,4,7,10-tetraazacyclododecane.

k) 24-mer Gd-N- (5-DO3A-yl-4-keto-3-azacaprooyl) -polyamide cascade complex N, N, N ', N', NN-six- [2- (trlysylamino) -ethyl] -trimazinic acid

8.13 g (0.5 mmol) of complex-forming acid described in example 1a), adjusted to pH 3 in water with dilute hydrochloric acid, with 2.17 g (6 mmol) of Gd2O3, it is stirred for 30 minutes at 80 DEG C., adjusted to a pH value after cooling, to 7 and desalted on an AMICON® YM3 ultrafiltration membrane. The retentate is finally subjected to membrane filtration and lyophilization.

Yield: 8.89 g (92.1% of theory).

Water content (Karl-Fischer): 9.6%

Gd (AaS) determination: 19.6%.

Elemental analysis (related to the anhydrous substance): calculated: C 40.26 × Z, 35 N 11.24 Gd 21.62 found: C 39.98 H 5.51 N 11.44 Gd 21.37.

Example 2

a) 4-brcmoproplonyl-5-alanyl benzyl ester

To 100 g (285 mmol) of the salt of e-Zoluevsulfonic acid with the benzyl β-alanine ester and 31.67 g (313 mmol) of triethylamine in 400 ml of methylene chloride at 0 ° C 53.65 g (313 mmol) of acid chloride are added dropwise 2-bromoeropion. The temperature is kept below 5 ° C. After the addition was complete, the mixture was stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. 5θ0 ml of ice water are added thereto, and the aqueous layer is adjusted to a pH value of 2 with 10% aqueous hydrochloric acid solution. The organic layer is separated, washed once with 300 ml of 5% aqueous hydrochloric acid each time and 400 ml of water. The organic layer is dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue is crystallized from dimsoproeyl ether.

Yield: 71.36 g (78% of theory) of a colorless crystalline powder.

Elemental analysis:

Calcd: C 48.46 H7.11 N4.35 Br 24.80 calculated. C 4-8.29 H 7.65 N 4.25 Br 24.61.

b) 1 - [5- (benzyloxycarbonyl) -1-methyl-2-keZo-5-azaeentyl] -1,4,7,1 O-tetraazacyclododecane

To 53.32 g (310 mmol) of 1,4,7,10-tetraazacyclododecane dissolved in 600 ml of chloroform, 50 g (155.2 mmol) of the title compound from Example 2a) are added and the mixture is stirred overnight at room temperature. 500 ml of water are added thereto, the organic layer is separated and washed twice more with 400 ml of water each. The organic layer is dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (circulation medium: chloroform / methanol / 25% aqueous ammonia solution = 10/5/1).

Yield: 38.39 g [61% of theory, based on the used compound 2 a)] of a slightly yellowish, ductile oil.

Elemental analysis:

Calculated: C 62.20 Η 8.0 O N 11.22 Found: C 62.05 H 8.81 N 17.15.

c) Sodium bromide complex compound with 10- [5- (benzoyloxycarbonyl) -1-rketyl-4-keto-5-azapentyl] -1,4,0-tri-(tert-butoxycarbonylmethyl) -1, 4,0,10-tetraazacyclododecane

To 20 g (49.32 mmol) of the title compound from Example 2b) and 17.28 g (163 mmol) of sodium carbonate in 300 ml of acetonitrile, 31.8 g (163 mmol) of tert-butyl bromoacetate are added and stirred for for 24 hours at 60 ° C. It is cooled to 0 ° C, the salts are filtered off, and the filtrate is concentrated to dryness. The residue was chromatographed on silica gel (circulation agent: ethyl acetate / ethanol = 10/1). The fractions containing the product are evaporated and the residue is recrystallized from diisopropyl ether.

Yield: 31.89 g (76% of theory) of a colorless crystalline powder.

Elemental analysis:

Calcd: C 55.05 H 7.70 N 8.23 Na 2.69 Br 9.40 Found: C 55.17 H7.85 N 8.10 Na 2.51 Br 9.30.

d) Sodium bromide complex compound with 10- [5- (kai'boxy) -1-methyl-'2-keto-3-azapentyl] -1,4,7-tricycle (I1-tcbutoxcarboniNslmethyl) -1,4 , 7.10-tetraazacylododecanem g (35.26 mmol) of the title compound from Example 2c) are dissolved in 500 ml of isopropanol and 3 g of palladium catalyst (10% PZ / C) are added. This was hydrogenated overnight at room temperature. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo and recrystallized from acetone.

Yield: 24.41 g (91% of theory) of a colorless crystalline powder.

Elemental analysis:

Calcd: C 50.52 H 7.82 N 9.21 Na 3.01 Br 10.52 Found C 50.41 H 7.95 N9.10 Na 2.91 Bir 10.37.

e) 24-meric N- (6-DO3A-yl-5-ketOc4-azaeNantoyl) cpolyamiZ cascaded on the N, N, N ', N', N, N-hexa [2- (trilylamino) -ethyl] -thiones trisminic acid

6.0 g (1 mmoz of zotobenzylonsykaebonylamma, thiNSaoyl, with the use of glacial acetic acid) are dissolved in glacial acetic acid and mixed with 33% hydrogen bromide in glacial acetic acid, while stirring. After 3 hours, the precipitation which has begun is complete with diethyl ether. The resulting bromine Zkrek 24-amines are washed with diethyl ether and dried in vacuo.

36.52 g (48 mmol) of the acid described in the previous example 2Z), dissolved in DMF, treated with: 7.35 g (48 mmol) of 1-hydroxybenzotnasole, 15.41 g (48 mmol) of TBTU (from Peboc Limited, UK) and 49.3 ml (288 mmol) of N-ethyldiisopropylamine and stirred for 20 minutes at room temperature. This solution is then mixed with the above-described (1 mmol) bromine 24-amine plug and stirred for 4 days at room temperature. This solution is concentrated in vacuo, the residual oil is cooled in an ice bath and mixed with trifluoroacetic acid, stirred overnight at room temperature, then precipitated with diethyl ether. The precipitate is dried in vacuo, taken up in water, adjusted to a pH value of 7, cleaned of low molecular weight components on an AMICON® YM3 ultrafiltration membrane, and the retentate finally subjected to membrane filtration and lyophilization.

Yield: 14.4 g (85% of theory).

Water content (Karl-Fischer): 8.7%.

Elemental analysis (related to the anhydrous substance): Calculated: C 46.82 H5.98 N 14.79 Na 10.59 Found: Ct 47.04 H 6.23 N 14.96 Na 10.26.

f) 24-mer Gd-N- (6-DC ^ 3Acy'lo-5-eeto-4-cazaenantoyl) -pollamlZu complex cascaded on the N, N, N ', N', N, N-six- [2- ( trilizsloamino) -etslo] ctróramiZu trimasnic acid

8.5 g (0.5 mmolz) of the complex of the compound, optoanegs in the previous composition. The pH value is 3 in water with dilute hydrochloric acid, add 2.17 g (6 mmol) GZA03, mix for 30 minutes at 80 DEG C., after cooling, it is adjusted to pH = 7 and desalinated on an AMICON® YM3 ultrafiltration membrane. The retenate is finally subjected to membrane filtration and lyophilization.

Yield: 8.50 g (88% of theory).

Water content (Karl-Fischer): 7.9%

GZ Assay (AaS): 19.4%.

Elemental analysis (referenced with ZO of the anhydrous substance): calculated: C41J2 1.25.22 N 12.99 Gd 21.21 Found: C 40.86 H 5.34 N 13.25 Gd 20.95.

187 712

Example 3

a) N, N'-two- (benzyloxycirbonyl) -3- [carboxymethoxyacetyl] ~ 3-aisapentaine diamine-1,5

37.14 g (100 mmoles) of the di-benzyloxycarbonylamino-amine described in Example 1a) are dissolved in DMF, and 17.4 g (150 mmoles) of diglycolic anhydride (from Janssen Chimica) and 21 are added in an ice bath. ml (150 mmol) of triethylamine and then stirred at room temperature overnight. This solution is evaporated in vacuo, the residue is taken up in ethyl acetate and shaken with dilute hydrochloric acid. The organic layer is dried over sodium sulfate and, after filtering from the drying agent, the filtrate is crystallized by adding hexane.

Yield: 41.4 g (85% of theory).

Elemental analysis:

calcd: C59J3 H 6.00 N8.66 Found: C6 58.99 H 5.93 N 8.70.

b) MNkNAN. ^ -tero-iB-CbenzyloxycarboonylaminoylA-1Mlbenzyloxycarboonylamino-ethyl ^ -keto ^ -oxacapryloyl] -cycylene

345 mg (2 mmol) of 1,4,7,10-tetraazacyclododecane (cyclene; from Fluka) are azeotropically dehydrated with toluene. To the cooled solution of cyclene in toluene is added, at room temperature, a solution of 4.88 g (10 mmol) of N N -div-benzyloxycarbonyl) - [carboxyethoxyacetyl] -3-azapent α-dihydrofuran-1,5 (example 3a) in tetrahydrofuran (THF) ) and 2.47 g (10 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (eEdQ; from Fluka) and stirred overnight. After completion of this reaction, the product is precipitated by addition of hexane, the solvent is decanted and the product is precipitated again from THF / hexane and then from THF / toluene. After drying in a vacuum, 2.78 g (68% of theory) of a pale yellow solid are obtained.

Elemental analysis:

Calcd: C8 60.93 H 6.29 NI 0.93 Found: C8 60.68 H 6.40 N 80.99.

c) Fully protected 32-amine benzyloxycarbonyl-32-polyamine, condensed with N, N ', N, N ^, -thiO- {8-benzyloxycarbonylamino)] 6] [2- (benzyloxycarbonylammoEethyl-2-keto-oxaoctanoyl-cyclane) and Na, N6-di- (lysyl) -lysine ("trilisines")

2.05 g (1 mn 1) of "Aonzyloxycorbonyl ammo", dipped in the form of 3d) and eozpu are brought into glacial acetic acid and mixed with 33% hydrogen bromide in glacial acetic acid while stirring. After 90 minutes with diethyl ether, the precipitation that has begun is complete, the octaamine hydrobromide formed is washed with ether, dried in vacuo and used in the reaction described below without further purification.

Yield: 1.6 g (quantitative).

9.4 g (10 mmelO kobe8p) aceoae6 "oriHzyn" and opNanop sa pi / wkUrzae lc ^ fc g (10 mmol) 1-hydroxybenzotriazole and 3.2 g (10 mmol) 2 - ("H-benzotriazolium-l) tetrafluoroborate) -III, 3,3-quart -methyluronium ^ (TBTU; from Peboc Limited, UK) is dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N] ethyldiisoaropylamine and 1.6 g (1 mmol) of the octaamine hydrobromide described above and stirred overnight at room temperature. After this reaction has ended, it is evaporated in vacuo and the residue is chromatographed on silica gel with dichloromethane / methanol (10: 1).

Yield: 6.0 g (72% of theory).

Elemental analysis:

calculated. C 63.32 H (5.76 NI 0.74 found: C 62.98 Η6.11 N 11.44.

d) 32-meric N] (5-DO3A-yl-4 · keto-3] azakαaroyl)] cascade polyamide based on the 32-mer amine described in the previous example 3c)

8.35 g (1 mmol) of 32-mer benzyloxycarbonylamine described in Example 3c) are dissolved in glacial acetic acid and mixed with 33% hydrogen bromide in glacial acetic acid while stirring. After 3 hours, precipitation began

The 187 712 is brought to completion with diethyl ether, the resulting 32-amine hydrobromide is washed with diethyl ether and dried in vacuo.

47.8 g (64 mmoles) of the acid described in Example 1h), dissolved in DMF, treated with: 9.8 g (64 mmoles) ^^^ y-hydroxybenzotriazole, 20.5 g (64 mmoles) TBTU (from Peboc Limited, UK) and 65.7 ml (384 mmol) of N-ethyldihydiproprosilic and stirred for 20 minutes at room temperature. This solution is then mixed with the above-described (1 mmol) 32-amine bromide and stirred for 4 days at room temperature. This solution is concentrated in vacuo, the residual oil is cooled in an ice bath and mixed with trifluoroacetic acid, stirred overnight at room temperature and then precipitated with diethyl ether. The precipitate is dried in vacuo, taken up in water, adjusted to a pH value of 7, purified from low molecular weight components on the AMICON YM3 ultrafiltration membrane, and the setentate is finally subjected to membrane filtration and lyophilization.

Yield: 17.2 g (76.4% of theory).

Water content (Karl-Fischer): 7.6%.

Elemental analysis (related to the anhydrous substance): Calculated: C 45.73 H 6 J 2 N 15.08 Na 10.61 Found: C 45.89 H 6.30 N 14.84 Na 10.31.

e) 32-me3y-my Gd-kompleom N- (5-DO3A-yl-4-keto-3-ezίd3aazokaZ-poly) madkayamide based on the 32-mesic amine described in example 3c)

10.4 g (0.5 mmc ^ lard acid komu1yOsdZreatczczczycaOpisonzpowpgorrapIύm prayd1zdzίe 3d), is adjusted in water with dilute hydrochloric acid for pH value = 3, infused with 2.89 g (8 mmoles) Gd203, mixed for 30 minutes at 80 ° C, after cooling, it is adjusted to a pH value of 7 and desalted through an AMICON® ultsαfiltsation YM3 membrane. The retentate is finally subjected to membrane filtration and lyophilization.

Yield: 12.1 g (91.1% of theory).

Water content (Karl-Fischer): 11.0%

Gd assay (AAS): 18.6%.

Elemental analysis (related to the anhydrous substance):

calculated: C 40.26 H 5.39 N 13.28 Gd 21.30 found: C 40.10 H5.1 1 N 1304 Gd 21.03. The ytterbium complex is obtained analogously with Yb2 (CO 3) 3: Elemental analysis (related to the anhydrous substance): calculated: C 39.42 H 5.28 N 13.00 Yb 22.94 found: C 39.29 115.40 N 12.811 Yb 22.65.

Example 4

a) p-tolnenzsulfaiaa of hexaethylene glycol monomethyl ether

To 20 g (67.49 mmoles) of yinomethyl hexaethylene glycol ether and 7.59 g (75 mmoles) of tetramethylamink in 200 ml of chloroform are added 14.3 g (75 mmoles) of p-toluenesulfonic acid chloride in portions at 0 ° C. then stirred for 4 hours at this temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (recycle medium: chloroform / methanol = 5/1).

Yield: 27.67 g (91% of theory) of a scaly glassy solid.

Elemental analysis:

Calcd: C 53.32 H 7.11 S 7.12 Found: C 53.15 H 7.70 S 7.03.

b) l-beazcloxy-5- (benzylzxycarboaylo) -y-c4lzsz-3-keto-4-azazentaa

To 100 g (296.4 mmol) of the benzyl glycine benzyl ester and 33.0 g (326.1 mmol) of tetraphthalamlak in 400 ml of methylene chloride, 76 g (326.1 mmol) are added dropwise at 0 ° C. γ-chloro-3- (benzytoxy) -propionic acid chloride (prepared according to Inorg. Chem., Vol. 31; 2422, 1992) and stirred for 2 hours at this temperature. 500 ml of ice water are added thereto, and the aqueous layer is adjusted to a pH value of 2. The organic layer is separated, washed once with 300 ml of 5% aqueous hydrochloric acid each time, 300 ml of 5% aqueous soda solution and 400 ml of water. The organic layer was dried over magnesium sulfate

187 712 and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (circulation agent: methylene chloride / hexane / acetone = 15/5/1).

Yield: 75.07 g (70% of theory) of a slightly yellowish, malleable oil.

Elemental analysis:

Calcd: C 66.07 H 5.57 N 3 ^ 1 C7 9.80 Found: C 66.17 H 5.65 N 3.75 C7 9.63.

c) 1- [4- (benzyloxycarbonyl) -1 - (benzyloxymethyl) -2-keto-3-iozabutyl) -1,4,7,10-tetraazacyclododecane g (193.5 mmol) of the title compound from example 4b) and 11.1 g (64.5 mmol) of 1,4,7,10-tetraazacyclododecane are dissolved in 70 ml of dimethylformamide and stirred for 2 days at 50 ° C. The mixture is evaporated to dryness in a vacuum, the residue is taken up in 700 ml of water and extracted twice with 250 ml of chloroform each. The organic layer is dried over sodium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (circulation agent: chloroform / methanol / 25% aqueous ammonia solution = 10/5/1).

Yield: 13.16 g (41% of theory, based on cyclene) of a ductile, colorless oil.

Elemental analysis:

Calcd: C 65.17 H 7.90 NI 4.07 Found: C 65.24 H 7.77 N 14.18.

d) Sodium bromide complex compound with 10- [4- (benzyloxycarbonyl) -1- (benzyloxymethyl) -2-keto-3-azabutyl] -1,4,7-tr- (III-nz.-butoxycarbonylmethyl) - 1,4,7,10-tetraazacyclododecane

To 13 g (26.12 mmol) of the title compound from Example 4c) and 9.14 g (86.2 mmol) of sodium carbonate in 200 ml of acetonitrile are added 16.81 g (86.2 mmol) of tertiary bromoacetate. butyl and is stirred for 24 hours at 60 ° C. It is cooled to 0 ° C, the salts are filtered off, and the filtrate is concentrated to dryness. The residue is chromatographed on silica gel (recycle medium: ethyl acetate / ethanol = 15/1).

Yield: 19.46 g (79% of theory) of a waxy solid.

Elemental analysis:

Calcd: C 57.32 H 7.38 N 7.43 Na 2.43 Br 8.47 Found: C 57.22 H 7.51 N 7.27 N3 2.33 Br 8.29.

e) Sodium bromide complex compound with 10- [4-carboxy-2-keto-1-hydroxymethyl-3-az, abutyl] -1,4,7-tr- (H1-tert-butoxycarbonylmethyl) -1,4, 7,10-tetraazaic cyclodoclekanern

To 19 g (20.15 mmol) of the title compound from Example 4d) in 300 ml of isopropanol were added 3 g of a palladium catalyst (10% Pd / C) and hydrogenated overnight at room temperature. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is recrystallized from acetone.

Yield: 13.06 g (85% of theory) of a colorless crystalline powder.

Elemental analysis:

Calcd: C 48.82 H 7.53 N 918 Na 3.00 Br 10.49 Found: C 48.71 H 7.68 N 9.03 Na 2.81 Br 10.23.

f) 10- [4- (benzyloxycarbonyl) -1 - (hydroxymethyl) -2-keto-3-azabutyl] -1,4,7-tr- (D1-butoxycarbonylmethyl) -1,4,7,10 -tetraazacyclododecane

To 13 g (17.04 mmol) of the title compound from Example 4e) and 6.11 g (18.75 mmol) of anhydrous cesium carbonate in 70 ml of dimethylformamide are added 3.42 g (20 mmol) of benzyl bromide and stirred overnight. at 50 ° C. It is cooled to 0 ° C and 700 ml of water are added to the total. It is then extracted twice with 300 ml of methylene chloride each time. The combined organic layers are washed twice with water, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (recycle medium: ethyl acetate / ethanol system).

187 712

Yield: 9.97 g (78% of theory) of a colorless, malleable oil.

Elemental analysis:

Calcd: C 60.86 H 8.47 N 9.34 Found: C 60.95 Η 8.11 N 9.21.

g) 10- [4- (benzyloxycarbcnyl) -1 -C0,0,8,11,14,17,2ϋ-he.eta-oxahenelcosanoyl) -2-Peto-3-dzabutal -] - L4,7-tri- (IΠ-rz.-but.oPsyParbofalomytall ^ ') - 1,4,7,10-tetraaz.acaPlododePaf

9.7 g (12.93 mmol) of the title compound from Example 4f) are dissolved in 50 ml of THF and 0.43 g (14.22 mmol) of sodium hydride (80% in paraffin) is added at -10 ° C. The mixture is stirred for 30 minutes at 0 ° C. Then 11.65 g (25.86 mmol) of the title compound from Example 4a) and 3.46 g (25.86 mmol) of lithium iodide are added. The mixture is stirred for 24 hours at room temperature. 3 ml of water is carefully added and then evaporated to dryness. The residue is deromatographed on silica gel (recycle medium: chloroform / methanol = 10: 1).

Yield: 12.1 g (91% of theory) of a glassy solid.

Elemental analysis:

calcd: C50.90 H 8.72 N 6.61 Found: C H 8.9L N 6.62,

h) 10- [1- (2,8,11,14,17,20-heptaoxahenelkcbanoylc) -2-keto-3-aza-4- (Parboxy) -butyl] -1,4i7-tri (ΠI-rz .-ButoxyParbonylmethyl) -1,4,7,10-tetracacyclododecaf g (11.67 mmol) of the title compound from Example 4g) is dissolved in 300 ml of isopropanol and 2 g of a palladium catalyst (10% Pd / C) are added. This was hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is crystallized from acetone / diisopropyl ether.

Yield: 10.18 g (93% of theory) of a waxy solid.

Elemental analysis:

Calcd C 15.3 H 8.92 N N 46 Found C 15.0 O H 9.03 N N 33.

i) 24-meracbny Gd-N- (5-DO3A-yl-4-Peto-3-lba-4,10,13,16,19,02,25-hepla ~ cxahyksdPozdfollo) -pcliamld N-matrix complex, N, N ', N', N, N-six- [2- (trisylamino) -ethyl] -trimezinic acid triamine

6.0 g (1 mmole of g4-merycgyea benzylonbakapbypdibcrlany, opiumed in glacial acetic acid) are dissolved in glacial acetic acid and mixed with 33% hydrogen bromide in glacial acetic acid while stirring. After 3 hours, the precipitation which has begun is complete with diethyl ether, the resulting 24-amine hydrobromide is washed with diethyl ether and dried in vacuo.

45.03 g (48 πιιτιο1 "mwasu, typed n gopwednim dfzykłeiizip 4h), loepurczea sżc in DMF, infuse with: 7.35 g (40 mmoles) of zotnasol 1-hydroxybene, 15.41 g (48 mmoles) TBTU (companies Peboc Limited, UK) and 49.3 ml (280 mmol) of N-ethyldiisoproylamphine and stirred for 20 minutes at room temperature. This solution is then treated with the above-described (1 mmole) 24-ιβ hydrobromide salt, and stirred for 4 days at room temperature. This solution is concentrated in vacuo, the residual oil is cooled in an ice bath and mixed with trifluoroacetic acid, stirred overnight at room temperature, then precipitated with diethyl ether. The precipitate is dried in vacuo, taken up in water, the pH is adjusted to 3 with dilute hydrochloric acid, treated with 0.70 g (24 mmol) Gd ^^ 3, stirred for 4 hours at 80 ° C, then After cooling down, the pH is adjusted to 7, purified from low molecular weight components on the AMICON® YM3 ultra-filtration membrane, and the retentate is finally subjected to membrane filtration and lyophilization.

Yield: 19.6 g (73.3% of theory).

Water content (Karl-Fischer): 8.3%.

Elemental analysis (related to the anhydrous substance): calculated: C 43.94 H 6.38 N 9.43 Upper 5.39 Found: C 44.27 H 6.22 Gd 11.00.

187 712

Example 5

a) 1,7-di- (trifluoroacetyl) -1,4,0-triazaheetaw

To a solution of 41.14 g (390 mmol) of 1,4,7-triazaheptane in 350 ml of tetrahydrofuran, 113.3 g (790 mmol) of ethyl trifluoroacetate were added dropwise at 80 ° C under nitrogen atmosphere. The mixture is stirred overnight at room temperature, concentrated in vacuo. The residual oil is crystallized from hexane.

Yield: 115 g (99.9% of theory).

Melting point: 68-70 ° C.

Elemental analysis:

Calcd C 32.55 H 776 F N 14.24 Found: C 32.63 11375 F 38.38 N 14.19.

b) 1,7-di-uoroacetyl) -4-benzyl oxy carbonyl 1- 1,4,7-triazaheptane

14.75 g (50 mmol) of the trifluoroacetyl compound prepared according to example 5a) and 8.3 ml (60 mmol) of triethylamine are dissolved in 120 ml of dichloromethane and cooled to 0 ° C. 7.5 ml (53 mmol) of benzylchloroformate (97%) dissolved in 2, ml of dichloromethane are then added dropwise while stirring. The mixture is stirred overnight at room temperature, the salts are extracted with distilled water, the dichloromethane solution is dried over sodium sulphate, concentrated to dryness in vacuo, and the residue is crystallized from ethyl ether / hexane.

Yield: 18.40 g (85.7% of theory).

Melting point: 131-132 ° C.

Elemental analysis:

total: C 44.76 H 3.99 F 26.55 N 9.79 Found: C 44.87 11.03 F 26.62 N 9.61.

c) Di-tert-butyl 5,9-di- (Illlr) -butoxycarbonylosket.yl) -6-besylcarbonyl-3,6,9-tπay.aundecanedicarboxylate

4.29 g (10 mmol) of the trifluoroacetyl ice prepared according to Example 5b) are dissolved in 30 ml of ethanol and mixed with 800 mg (20 mmol) of sodium hydroxide in 10 ml of distilled water. The mixture is stirred for 3 hours at room temperature, concentrated to dryness in a bath temperature of 40 DEG C. under vacuum, the residual water is removed by azeoZroeoke distillation with isopropanol and the residue is taken up in 30 ml of dimethylformamide. Subsequently, 6.9 g (50 mmol) of potassium carbonate and 9.7 g (50 mmol) of N-tibuzyl bromoacetate and 4-benzyloxycarbonyl-1,4,4,0-triazaheethane are added and the mixture is alkylated at room temperature within night. The dimethylformamide is then stripped off in an oil vacuum pump, the residue is taken between the layers of water and dichloromethane, the organic solution is dried over sodium sulphate, concentrated to dryness in vacuo, and the residue is purified by chromatography on silica gel. The title compound is eluted with ethyl acetate / hexane. A foam product is obtained.

Yield: 6.49 g (93.6% of theory).

Elemental analysis:

Calcd: C 62.32 H 8.57 N 6.06 Found: C162.41 H 8.66 N6.11.

d) 5,9-di- (2nd tier-butoxycarbonylcmethyl) -5,6,9-triazaundecanedicarboxylic acid, tertiary butyl

3.5 g (5 mmol) of the compound prepared according to Example 5c) are dissolved in 100 ml of ethanol, treated with 200 mg of Pearlman's catalyst (Pd 20% on activated carbon) and hydrogenated until the calculated amount of hydrogen has been absorbed. The catalyst is filtered off under reduced pressure and the filtrate is concentrated to dryness in vacuo. The title compound is obtained as a white foam.

Yield: 2.80 g (99.9% of theory).

Elemental analysis:

Calcd: C 160.08 H 9, R 4, N 7.11 Found: C 60.02 H 9.62 N 7.56.

187 712

e) 3,9-ywu- (HI-sz.-butoxycasbonylmethklo) -6- [1- (ethoxycasbonyl) -etclz] -3,6,9-tslazaundecα-decarboxyclaa yw-IH-sh.-butyl

5.60 g (10 mmol) of the amine compound prepared according to Example 5d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.17 g (12 mmol) of ethyl γ-dimopoxylate were added thereto, and stirred overnight. It is then poured into ice-water, extracted with ethyl acetate, the organic solution is dried over sodium sulphate and concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. An ethyl acetate / hexane mixture serves as the eluent.

Yield: 4.18 g (63.4% of theory).

Elemental analysis:

Calcd: C 60.07 H 9.32 N 6, H 7 Found: C 60.18 H 9.40 N 6.31.

f) 7,9-y- (pl-butoxyyabonylmethyl) -6- [l- (yasboysk) -ethyl] -7,6,9-triazaundekaaoyicarboksklaa doublet. -butyl

6.60 g (10 mmol) of the compound prepared according to Example 5e) are dissolved in 50 ml of ethanol. A solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added thereto and the mixture is stirred for 3 hours at 50 ° C. According to the thin film chromatogram, the saponification is quantitative. It is concentrated to dryness, traces of water are removed by co-distillation with ethanol and the residue is dried at 40 ° C in vacuo. The title compound is obtained as a white powder. The white residue obtained is dissolved in 80 ml of moist ethanol (9: 1) and mixed with a solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water while stirring. It is concentrated to dryness, the soluble parts are taken up in butanol and concentrated to dryness under a vacuum again. The residue is extracted with toluene. The organic solution is concentrated to dryness in vacuo to afford the title compound as a foam.

Yield: 5.35 g (84.7% of theory).

Elemental analysis:

Calcd: C 58.9) 3 H 1.00 N 6.65 Found: C 59.01 H9.16 N 6.60.

g) Sodium salt of y4-mesic N- {N, N-di- [y- (N, N-di- (carboxymethyl) -aminoethyl] -alanyl} -polyamine cascade N, N, N ', N', N, N-six- [y- (tsojllzkloamino) -ethklo] -tsojamiyu of thjmeinic acid

6.0 g (1 m 1) of dol-benzylpn-ykiybynylzine, ontsaozZ sanpadpadyke μ), are dissolved in glacial acetic acid and mixed with 33% bromovoyoane in glacial acetic acid while stirring. After 3 days, the beginning of precipitation is finished with diethyl ether, and the resulting 24-amines are washed with diethyl ether and dried in a vacuum.

30.33 g (48 mmol) of the acid described in the previous example 5f), dissolved in DMF, treated with: 7.35 g (48 mmol) of 1-hydroxybenzociazole, 15.41 g (48 mmol) of TBTU (from Peboc Limited, UK) and 49.3 ml (288 mmol) of N-ethylde ^, uisoplZkloamlak, and stirred for 20 minutes at room temperature. This solution is then mixed with the above-described (1 mmol) bsomowzdosklpm γ4-amlnk and stirred for 4 days at room temperature. This solution is concentrated in vacuo, the residual oil is cooled in an ice bath and mixed with trifluoroacetic acid, stirred overnight at room temperature, then precipitated with diethyl ether. The precipitate is dried in vacuo, taken up in water, adjusted to a pH value of 7, cleaned of low-particulate components on the AMICON® YM3 ultrafiltration membrane, and the pententate is finally subjected to membrane filtration and lyophilization.

Yield: 11.0 g (86.3% of theory).

Water content (Kαsl-Fisches): 8.2%.

Elemental analysis (related to the anhydrous substance): Calculated: C 42.87 H5.41 N 11.96 Na 12.08 Found: C 42.78 H5.66 N 1241 ^ a118 ^^.

187 712

h) Sodium salt of the 24-merionic Gd-complex N- {N, N-dNU-t2- (N, N-dwNtkwboxymetzin) -aminoetzio] -aianyio} -poilamld cascade on the N, N, N ', N' matrix, Trimazinic acid N, N-six- [2- (trimazino-amino] tetzio]

8.13 g (0.5 mmoles) of kympleksplvórcneyo, opίsnnegowpoo8yedoim of the plaque 5 gC. adjust the pH to 3 in water with dilute hydrochloric acid, add 2.17 g (6 mmol) of Gd2O3, stir for 30 minutes at 80 ° C, adjust to the pH value after cooling = 7 and desalted through an AMICON® YM3 ultrafiltration membrane. The retentate is finally subjected to membrane filtration and lyophilization.

Yield: 8.0 g (90.5% of theory).

Water content (Karl-Fischer): 7.5%

Gd (AaS) determination: 21.0%.

Elemental analysis (related to the anhydrous substance): calculated: C 35.93 H 4.38 N 10.03 Gd ^^ 0 ^ 9 Na 3.38 Found: C 35.71 H 4.65 N 9.88 Gd 22, 84 to 3.50.

Example 6

a) 3.9td2- (Π) tbutn> xykarbsmyiometyio) -5-benzylox- carbonylmethyl-3559-tπazaundecanedicarboxylate di-IL-tbutzovz

5.60 g (10 mmol) of the amine compound prepared according to Example 5d) are dissolved in 30 ml of dimethylformamide. Then 1.66 g (12 mmol) of potassium carbonate and 2.58 g (12 mmol) of benzyl bromoacetate are added thereto at room temperature, and the mixture is stirred overnight. It is then poured into ice-water, extracted with ethyl acetate, the organic solution is dried over sodium sulphate and concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. An ethyl acetate / hexane mixture serves as the eluent.

Yield: 6.32 g (89.3% of theory).

Elemental analysis:

Calcd: C 64.65 H 9.00 N 5.95 Found: C 664-, N 2 H 9.07 N 5, N (0.4)

b) 3,9-two- (third-tertiary butoxycarbonzlometzlo) -3 (6,5-triazaundecane dicarboxylic acid, tertiary butylated)

7.08 g (10 mmoles) of the ciderite prepared according to example 6 a) are dissolved in 100 µl of ethanol, and 0.4 g of Pearlman's catalyst (Pd 20% on activated carbon) is added. The mixture is hydrogenated until 224 ml of hydrogen have been absorbed, the catalyst is filtered off under reduced pressure, washed thoroughly with ethanol and the solution is concentrated to dryness in vacuo. The product is obtained in the form of a foam which is crystallized from ethyl ether / hexane.

Yield: 6.87 g (97.3% of theory).

Melting point: 73-75 ° C.

Elemental analysis:

Calcd: C 57.85 H 9.00 N 5.99 Found: C 57.91 H9.1 N 6.01.

c) sodium salt of 32-mer N- {N (Ntdwut [2t (N-N-di- (carboxymethyl) amitnoetyio] tglycyl} polamide cascade based on the 32tmeric amine described in example 3c)

8.35 g (1 mmol) of the 32tmeric Zendyloesyearbnnamine described in Example 3c) are dissolved in glacial acetic acid and mixed with 33% hydrogen bromide in glacial acetic acid while stirring. After 3 hours, the precipitation which has begun is complete with diethyl ether, the resulting hydrobromide 24-6ρ1νζ is washed with diethyl ether and dried in vacuo.

39.5 g (64 mm4lp) of PU acid in improved 6 ^ 1 drzpkladzye 6 ^ 1 is dissolved in DMF, add with: 9.8 g (64 mmoles) 1-hzdroxy ZenzntriadnlU (20.5 g (64 mmoles) TBTU (from PcZoc Limited, Great Britain) and 55 (5 ml (384 mmol) N-ethyldiisoprinamine 1 for 20 minutes are stirred at room temperature. This solution is then mixed with 32-amma hydrobromide as described above (1 mmol) and stirred for 4 days at room temperature. This solution was concentrated in vacuo, the residual oil was cooled

187 712 in an ice bath and quenched with trifluoroacetic acid, stirred overnight at room temperature, then precipitated with diethyl ether. The precipitate is dried under vacuum, taken up in water, adjusted to a pH value of 7, cleared of low molecular weight components on the YM3 AMICON® ultrafiltration membrane, and the retentate finally subjected to membrane filtration and lyophilization.

Yield: 15.7 g (78.6% of theory).

Water content (Karl-Fischer): 9.0%.

Elemental analysis (related to ZO of the anhydrous substance):

Calcd: Ct 41/77 H 5.24 N 12.33 Na 12.14 Found: C4f49 H 5.36 N 12.49 Na 11.93.

d) Sodium salt of HZ-meric Gd- ^ Gpleosz N- {N, Ncdwu- [Z- (N, N-dNu - ZgrUoxymethyl) camiNoethyl] -glycyl} cpolyamide cascade on a 32-merger amine matrix, described in the example 3c)

10.0 g (0.5 mmol a) Zwasu kgmuleOstwercz, optsarlogo in poprgednim scale-ye 6 c), adjust in water with dilute hydrochloric acid to pH = 3, add 2.89 g (8 mmoles) Gd ^ ^ 3, stirred for 30 minutes at 80 [deg.] C, cooled down, adjusted to a pH of 7 and desalted on an AMICON® YM3 ultrafiltration membrane. The retentate is finally subjected to membrane filtration and lyophilization.

Yield: 10.9 g (90.9% of theory).

Water content (Karl-Fischer): 9.5%.

Gd determination (AAS): 20.9%.

Elemental analysis (related to the anhydrous substance):

Calculated: C 34.98 H4.24 N 10.33 Gd 23.19 Na 3.39 Found: C 35.20 H 4.08 N 10.46 Gd 22.89 Na 3.60.

Example for in vivo comparison with extracellular contrast agent

In the test given below, the usefulness of the compound described in Example 1k) as a blood-aool agent is demonstrated.

A group of five male rats (Schenng-SPF) weighing 300-350 g each serve as experimental animals. Before the test, the abdomen is opened, the intestine is displaced, and then the renal vessels (arterial + venous) are ligated through the posterior peritoneum by means of a surgical needle. Then the abdominal cavity is closed again. After this, 0.3 ml (each time 50 mmol / L) of a solution of the following contrast agent is administered intravenously to each animal: a mixture of 1 part of the compound from example 1k), then called compound 1, and 1 part of the dysprosium complex 10- (1chdroxgmethyl-y , 3-ZwuhyZroxyaropyl) -1,4,7-tr- (carboxymethyl) - 1,4,7,10 ctetraazacgclododecan, produced by analogy to the provision in European patent application EP 448 191, then called compound 2. Through the catheter in Arteria oarotis communis it takes blood samples are obtained at the following time points: 15, 30, 45, 60, 90 seconds, 3, 5, 10, 1, minutes pi In the blood samples obtained, the concentrations of gadolinium (Gd) and dysprosium (Dy) are measured in parallel using atomic emission spectrometry (ICE-AES). In the blood space, the residual proportion of the injected contrast agent compound 1 (Gd) and compound 2 (Dy, reference substance) can be compared in the same animal due to the different labeling. Since renal excretion is not possible, the decrease in blood concentration may only be due to dispersion into the blood space and diffusion into the interstitial tissue. (The abbreviation p.i. means after injection).

Results: Compound 1 diffusion in the interstitial tissue is markedly slowed down compared to the extracellular contrast agent, ie compound 2 (see figure 1).

The extracellular contrast agent (compound 2) diffuses so quickly into the interstitial space that after only 3-5 minutes p. equilibrium is achieved (indicated by a constant blood level). In contrast, with the cascade polymer (compound 1), not only is a higher blood concentration always measured (an indication of a lower dissipation volume), but even over the entire test period of 15 minutes,

187 712 still no equilibrium (an indication of a very slow diffusion into the interstitial tissue). This means that compound 1 acts as the contrast medium of the blood pool.

Figure 1 Measured blood concentrations of element Gd (compound 1) and element Dy (compound 2) in rats (n = 5) with ligated renal vessels

Gd (± standard deviation)

Dy (± standard deviation)

Example of MR angiography in rabbits

The compound described in Example 1k was tested in rabbits (CH. R. Kisslegg, <4 kg body weight) in the MR angiography test (Ganzkórper MRT System Siemens Vision. 1.5 Tesla, FISP 3D; TR: 400 ms; TE 15 ms; throw angle : 45 °; crown).

In the pre-contrast image (see photo), only one or two larger vessels (eg Aorta abdominalis) are visible with rather low contrast (the intensity of the SI signal of these vessels against the background). After intravenous administration of 50 IU Gd / kg body weight of the compound described in Example 1k, a marked increase in contrast (vessel SI / background SI) and a multitude of small and small blood vessels (e.g. A. and V. femoralis, A. and V. mesenterica caudalis, A. and V. renalis, A. and V. subrenalis, etc.), which were undetectable prior to administration of the contrast medium.

187 712

Pre. Iminp.i. 9 mins. 30 mins. Contrast medium: 24-Gd-GlyMeDOTA-cascade polymer

A dose: 50 μηιοΙ Gd / kg body weight

FISP 3D micrographs (TR 50 msec, TE 6 msec, projection angle 45'j - An example of lymph node accumulation in guinea pigs

The compound of the invention, described in Example 1k, was tested 30 minutes-24 hours after subcutaneous administration (10 gm of Gd / kg body weight, subcutaneously in the hindpaw) in agitated guinea pigs (complete Freund-adjuvant; 0.1 ml each time intramuscularly) in the right and left thigh and shin; 2 weeks prior to test substance administration) for its accumulation in the lymph nodes in three consecutive lymph node stations (popliteal, inguinal, iliac). The following results were obtained (determination of gadolinium concentration using ICP-AES):

The moment of retrieval from the lymph nodes Gadolinium concentration in three consecutive lymph node stations [amol / l] [% dose / g tissue] knee-length inguinal hip ratio 30 min p. I. 921 μmol / l 20.1% 387 μmol / l 8.5% 215 (imol / 1 4.7% 10.4.2: 2.3 90 min p i 659 μmoL0 14.4% 120 µmol / 1 2.6% 68 μmoL0 1.5% 10.1,8.1.0 4 h p. I. 176 µmol / 1 3.9% 79 (imol> ^ 1 1.7% 47 jmoU 1.0% 10: 4.5-2.7 24 h p. I. 62 (Mmol / i 1.4% 13 limol / l 0.3% 28 μmol / i 0.6% 10: 2.1: 4.5

187 712

Publishing Department of the UP RP. Circulation of 70 copies. Price PLN 6.00.

Claims (5)

Patent claims 1. Cascade polymer complex compounds, containing a) Complex-forming ligands of general formula I A- {X- [Y- (Z- <WK _w > z _y ] x} a (I), where A as the nitriding cascade core of the basic multiple of a represents a nitrogen atom, groups with the formulas N-CH ₂ (CH ₂ ) N-CH ₂ - (CH ₂ ) _n U ¹ , U ' U '/ • N ^X u ² N-CH ₂ - CH ₂ -N CH. CH (CH ₂ ) N - ^ - CH 9 - CH o 2X - ^ P ^{2 2} (CH ₂ ) _m N o u ² u ^with u I and CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ N— CH 9CH 9 — N — CH 9CH 9 — N — CH ₂ CH ₂ —N, I 2 2! 22, \ U ² U ² CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH {uu 187 712 R C (M — N, Z \ ² where m is 1-3, n is 1-3, p is 0-3, 4 187 712 U ¹ is Q ^] or E, U ² is Q ² or E and E is a group Ω ¹ / - (CH ₂ ) _O -CH ₂ -N \ Q ² Where o is the number 1, Q ^L is a hydrogen atom or Q2 and ^Q2 is a direct bond, hereinafter M is -CH2-, -CO- or -CH 2 CO-, R ° represents the group -CH ₂ NU ^] U 2, CH 3 - or NO ₂ , the amount of Q 2 being the fundamental multiple of a, X and Y independently of each other denote direct bond or X 1 Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w are independent of each other -CH2CH2NH-; -CH2CH2N <; -COCH (NH -) (CH2) 4NH-; -COCH (N <) (CH ₂₎ 4 N <; -COCH2OCH-> CON (CH ₂ CH ₂ NH-) ₂ ; -COCH2OCH2CON (CH2CH2N &lt;)2; -COCH ₂ N (CH ₂ CH ₂ NH-) ₂ ; -COCH2N (CH ₂ CH ₂ N <) 2; -COCH ₂ NH-; -COCH2N <; -COCH2CH2CON (CH 2 CH ₂ NH-) 2; -COCH2CH2CON (CH ₂ CH 2 N <) _2; -COCH2OCH ₂ CONH-C ₆ H4-CH [CH2CON (CH ₂ CH ₂ NH-) 2] 2; -COCH ₂ OCH2CONH-C6H4-CH [CH2CON (CH2CH2N &lt;) ₂ ] 2; -COCH _? CH ₂ CO-N ^t H-C 6 H 4 -CH [CH 2 CON (CH ₂ CH ₂ NH 2 ₂ ] ₂ ; -COCH2CH ₂ CO-NH-C6H4-CH [CH2CON (CH2CH2N <) 2] _2; -CONH-C6H4-CH [CH2CON (CH ₂ CH ₂ NH-) _{2] 2;} -C0NH-C6H4-CH [CH2CON (CH2H4) ₂ ] ₂ ; -COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <; groups of formula con (CH ₂ CH ₂ n <) ₂ 187 712 CON (CH ₂ CH ₂ NH-) ₂ O (C ^ CH ₂ O) C ^ CH ₂ NHO (C ^ CH ₂ O) CH ₂ CH ₂ NH- -C 0 (CH ₂ CH ₂ O) Cl 2 CH ₂ N < O (CH ₂ CH ₂ O) CH ₂ CH ₂ NHO (CH ₂ CH ₂ O) CH ₂ CH ₂ N < 187 712 K denotes the radical of the complexing agent, a denotes the number 2-12, x, y, z and w independently of each other denote the number 1-4, provided that at least two reproductive units are different and that there is a relationship for the product of multiple 16 <a -x -y - z - w <64, b) at least 16 element ions with the order number 20-29, 39, 42, 44 or 57-83, c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and d) Amine terminal groups cited, if any, characterized by the following features: with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K is a radical of the general formula IA R ¹ OOC-R ² HC r3 N-CH ₂ - CH ₂ -N CH ₂ CHo II ⁰ CH ₂ ch ₂ N-CH ₉ - CH, -N CHR ² -COOR ¹ CHr2-COOr1 (IA) where R ¹ independently of each other are a hydrogen atom or the equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83, R ² is hydrogen, methyl or ethyl, which is optionally substituted by 1 to 2 hydroxyl groups and one carboxyl group, R ³ is a group R ² R ⁴ I and -ch-co-nu ⁶ -t R ⁴ is a straight chain, branched, saturated or unsaturated C 1 -C 3 alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 phenylene group, 1 phenyleneoxy group and / or optionally substituted with 1-5 hydroxyl groups, 1-3 carboxyl groups 1 phenyl group U represents a chain _Ci-C2 o-alkylene group containing -CH2-, -CH2NHCO-, -NHCOCH2O-, -NHCOCH2OC6H4-, -N (CH2C02H) -, -NHCOCH2C6H4-, H4- -micsnhc _6, -CH2OC6H4-, -CH2CH20- and / or substituted by -COOH, -CH 2 COOH, preferably is a -CH ₂ -, -CH2CH2-, -CH2CH2CH2-, -C6H4-, -CóHio-, -CH2C6H5-, -CH2NHCOCH ₂ CH (CH2CO2H) - C6H4-, -CH2NHCOCH2OCH2-, -CH2NHCOCH2C6H4-, T represents the group -CO-a, -NHCO-a or -NHCS-a, and a represents the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W. 2. The compound according to claim 1, wherein the 24-metal GN-complex N- (S -D03A-yl-4-keto) -3-azacapiOyl) -po) cascade N, N matrix, N ', N', N, N-hex- [2- (trlysylammo) ethyl] -trimazinic acid. 187 712 3. A pharmaceutical composition containing an additive commonly used in galenic pharmacy and an active substance, characterized in that the active substance is a cascade polymer complex compound containing a) Complex-forming ligands of general formula I A- {X- [Y- (Z- <WK _w > ₂ ) _y ] _x j _a (I), where A as the nitriding cascade core of the basic multiple of a represents a nitrogen atom, groups with the formulas U ¹ AT' AT' N-CH ₂ (CH ₂ ) AT' N — CH ₂ - (CH ₂ ) _n AT' N-CH ₉ —CHoch ₂ -N ch ₂ (? ^H 2) m n-53-ch ₂ —ch ₂ —N, AT' AT' AT' AT' -J P CH ₂ CH 2_ N — CH ₂ CH ₂ —14 — CH ₂ CH ₂ 14— CH ₂ CH ₂ —14 — CH ₂ CH ₂ —14 — CH ₂ CH ₂ —N uCH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ AT' AT' 187 712 / AT R ° C (MN \ ² E where m is 1-3, n is 1-3, p is 0-3, U ¹ is Q * or E, 187 712 U ² is Q ² or E and E is a group Q '/ - (CH ₂ ) _O -CH ₂ -N \ Q ² where o is the number 1, Q * is hydrogen or Q ² , and Q2 is a direct bond, further M is -CH2-, -CO- or -CH2CO-, R ° represents the group -CH2NU V, CH3- or NO2, the amount of Q2 being the fundamental multiple of a, X and Y independently of each other denote direct bond or X and Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w denote independently of each other -CH ₂ CH ₂ NH-; -CH ₂ CH ₂ N <; -COCH (NH -) (CH2) 4NH-; -COCH (N <) (CH ₂₎ 4 N <; -COCH2OCH2CON (CH 2 CH ₂ NH-) 2; -COC ^ OC ^ CONCCHiCHaNch; -COCH ₂ N (CH, CH ₂ NH-) ₂ ; -COCH, N (CH ₂ CH ₂ N 6) ₂ ; -COCH2NH-; -COCH2N <; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ NH-) 2; -COCH ₂ CH ₂ CON (CH, CH ₂ N <) 2; -COCH2OCH2CONH-C ₆ H4-CH [CH2CON (CH2CH2NH-) ₂ ] ₂ ; -COC2 OC2COhM-CeHrCHEC2C2C2NkHH; -COCH2CH2CO-NH-C6H4-CH [CH ₂ CON (CH ₂ CH ₂ NH-) 2] ₂ ; -COCH ₂ CH, CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N 6) ₂ ] ₂ ; -C0NH-C6H4-CH [CH ₂ CO N (CH ₂ CH ₂ NH-) ₂ ] ₂ ; -CONH-C6H4-CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ; -COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <; groups of formula -coch ₂ oh ₂ con CON (CH ₂ CH ₂ N <) ₂ 187 712 -CON CON (CH ₂ CH ₂ NH-) ₂ CON (CH ₂ CH ₂ NH-) ₂ CON (CH ₂ CH ₂ N <) ₂ -CONH · 187 712 K denotes the radical of the complexing agent, a denotes the number 2-12, x, y, z and, independently of each other, denote the number 1-4, provided that at least two reproductive units are different and that the relationship is between 16 <a x y z w <64, b) at least 16 element ions with the order number 20-29, 39, 42, 44 or 57-83, c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and (d) optionally acylated amino terminal groups, characterized by the following features: with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K is a radical of the general formula IA R ¹ OOC-R ² HC _r 3 N-CH ₂ - CH ₂ -N CH ₂ CHn II ² CH ₂ ch ₂ N-CH, - CHn-N CHR ² -COOR ¹ CHR ² -COOR ¹ (IA) where R ^1, independently of each other, represent a hydrogen atom or an equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83, R ² is hydrogen, methyl or ethyl, which is optionally substituted by 1-2 hydroxyl or 1 carboxy group, R ³ is a group R ² R ⁴ I and -ch-co-nu ⁶ -t, R ⁴ is a straight chain, branched, saturated or unsaturated C 1 -C 3 alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 phenylene group, 1 phenyleneoxy group and / or optionally substituted with 1-5 hydroxyl groups, 1-3 carboxyl groups 1 phenyl group U ⁶ is a C 1 -C 20 -alkylene chain containing the groups -CH2-, -CH-NHCO-, -NHCOCH2O-, -NHCOCH2OC6H4-, -N (CH2CO2HK -NHCOCH2C6H4-, -NHCSNHC6H4-, -CH2OC6H4-, -CH2CH20- and -CH2CH20-, / or substituted with groups -COOH, -CH2COOH, preferably is the group -CH2-, -CH2CH2-, -CH2CH2CH2-, -C6H4-, -C6H10-, -CH2C6H5-, -CH2NHC0CH ₂ CH (CH2C02H) -C6H4-, -CH2NHCOCH2 -, -CH2NHCOCH2C6H4-, T represents the group -CO-a, -NHCO-a or -CHCS-a, and a represents the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W. 4. Use of a cascade polymer complex compound containing a) Complex-forming ligands of general formula I A- {X- [Y- (Z- <WK _w > _z ) _y ] _x } _a (I), 187 712 in which A as the nitriding cascade core of the basic multiple of a represents a nitrogen atom, groups with the formulas U ¹ u ¹ u N-CH ₂ (CH ₂ ) uNCH. N-CH ₂ - (CH ₂ ) _n U ¹ -U · • N ears ₂ —ch ₂ (CH ₂ ) N - => CH ₉ - ch ₉ 2 / P ^{2 2} -N CHo I <θ ^Η 2> m -N AT' ΙΓ AT' CH ₂ CH ₂ —N —- CH ₂ CH ₂ —N — CH ₂ CH ₂ , N— CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N AT' AT' N u ^: CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ u- 187,712 where m is 1-3, n is 1-3, p is 0-3, U1 is Q * or E, 9 ^ 9 U is Q or E and E is a group Ω ¹ / - (CH ₂ ) _O -CH ₂ -N \ Q ² where o is the number 1, Q] is hydrogen or Q ² , and q2 is a direct bond, further M is -CH2-, -CO- or -CH ₂ CO-, R ° represents the group -CH ₂ NUiU ² , CH3- or NO2, the amount of Q2 corresponding to the fundamental multiple of a, X and Y independently of each other denote direct bond or X and Y as reproductive cascade unit of reproductive multiple x or y and Z 1 W as reproductive cascade unit of reproductive multiple z or w denote independently of each other 187 712 -CH ₂ CH ₂ NH-; -CH ₂ CH ₂ N <; -COCH (NH -) (CH ₂ ) ₄ NH-; -COCH (N <) (CH ₂₎ 4 N <; -COCH ₂ OCH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ OCH ₂ CON (CH ₂ CH ₂ N <) ₂ ; -COCH ₂ N (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ N (CH ₂ CH ₂ N <) ₂ ; -COCH ₂ NH-; -COCH ₂ N <; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ N <) ₂ ; -COCH ₂ OCH ₂ CONH-C ₆ H4-CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ; -COCH ₂ OCH ₂ CONH-C ₆ H4-CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ 1 ₂ ·, -COCH ₂ CH ₂ CO-NH-C ₆ H4-CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ; -COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ; -CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-)] ₂ -CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ; -COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <; groups of formula CON (CH ₂ CH ₂ N <) ₂ 187 712 OCC ^ CHJOJC ^ CHJNH-. OCCHjCH ^ Ch ^ CH ^ * K denotes the radical of the complexing agent, a denotes the number 2-12, x, y, z and w independently of each other denote the number 1-4, provided that at least two reproductive units are different and that for the product of multiple the relationship 16 <a x y z w <64, b) at least 16 element ions with the order number 20-29, 39, 42, 44 or 57-83, c) optionally cations of inorganic or organic bases, amino acids or amino acid amides, and (d) optionally acylated amino terminal groups, characterized by the following features: with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K is a radical of the general formula IA R ¹ OOC-R ² HC r3 N-CH ₂ - CH ₂ N CH ₂ CH, II ch ₂ ch ₂ N-CH, - CH, N CHR ² -COOR ¹ CHRZ-COOR ¹ (IA) in which R ^1, independently of each other, represent a hydrogen atom or an equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83, 187 712 R represents a hydrogen atom, a methyl or ethyl radical, which is optionally substituted with 1-2 hydroxyl groups or 1 carboxyl group, R ³ is a group R ² R ⁴ I and -ch-co-nu ⁶ -t R ⁴ is a straight, branched, saturated or unsaturated C 1-10 alkyl chain which is optionally interrupted by 1-10 oxygen atoms, 1 Cenylene group, 1 Cephaloxyl group, and / or optionally substituted with 1-5 hydroxyl groups, 1-3 carboxyl groups, 1 phenyl group, Ir is a chain Ci-o-alkylene group containing -CH2-, -CH2NHCO-, -NHCOCH2O-, -NHCOCH2OC6H4-, -N (CH2C0 ₂ H) -, -NHCOCH2C6H4-, -NHCSNHC6H4-CH2OC6H4- -CH2CH2O- and / or substituted with -COOH, -CH2COOH groups, preferably is -CH2-, -CH2CH2-, -CH2CH2CH2-, -C6H4-, -C6Hio-, -CH2C6H5-, -CH2NHCOCH2CH (CH2CO2H) -C6H4-, -CH2NHCOCH2OCH2- CH2NHCOCH2C6H4-, T represents the group -CO-a, -NHCO-a or -NHCS-a, aa represents the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W, for the production of agents for dlagfostaP1-NMR or for X-ray diagnostics, especially conventional methods and computed tomography . 5. Use of a cascade polymer complex compound containing a) PcmelePs forming ligands of general formula I A- {X- [Y- (Z- (WK _w ) _z ) _y ] _x } _a (I), where And as the azcohoid core of the fundamental multiple of a is a nitrogen atom, groups of the formulas N-CH ₂ (CH ₂ ) N— CH ₂ - (CH ₂ ) _n —N / sl \ AT' U ¹ uU 'uN-CH ₉ —CH ₉ -N Φ I ch ₉ 1 ² ch ₉ | ^with ( ^CH 2) m (Ch ₂ ) _with rP> ^ - CH ₂ —ch ₂ - - N 187 712 u ^z u ² I and CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ N— CH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH ₂ —N uCH ₂ CH ₂ —N — CH ₂ CH ₂ —N — CH ₂ CH / AT' And u- WITH R ° C (M — N 187 712 Ε where m is 1-3, n is 1-3, p is 0-3, U ¹ means ζ) ¹ or E, U2 is Q2 or E and E is a group Ω ¹ / - (CH ₂ ) _o —ch ₂ —n \ Q ² where o is the number 1, Q 'is hydrogen or Q ² , and Q ² is a direct bond, further M is -CH ₂ -, -CO- or -CH ₂ CO-, R ° represents the group -CHNU ¹ ! ', CH3- or NO ₂ , the amount of Q ² being the fundamental multiple of a, X and Y independently of each other denote direct bond or X and Y as reproductive cascade unit of reproductive multiple x or y and Z and W as reproductive cascade unit of reproductive multiple z or w denote independently of each other -CH ₂ CH ₂ NH-; -CH2CH2N <; -COCH (NH -) (CH2) 4NH-; -COCH (N <) (CH2) 4N <; -COCH ₂ OCH ₂ CON (CH ₂ CH ₂ NH-) 2; -COCH2OCH ₂ CON (CH ₂ CH2N &lt;)2; -COCH ₂ N (CH2CH2NH-) 2; -COCH2N (CH ₂ CH 2 N <) 2; -COCH2NH-; -COCH2N <; -COCH2CH ₂ CON (CH2CH2NH-) 2; -COCH2CH2CON (CH ₂ CH 2 N <) 2; -COCH ₂ OCH ₂ CONH-C6H4-CH [CH ₂ CON (CH2CH2NH-) 2] ₂ ; -COCH ₂ OCH ₂ CONH-C6H4-CH [CH ₂ CON (CH ₂ CH ₂ N <) 2] ₂ ; -COCH2CH2CO-NH-C6H4-CH [CH ₂ CON (CH2CH2NH-) 2] 2; -COCH2CH ₂ CO-NH-C6H4-CH [CH2CON (CH2CH2N <) 2] 2 ·; -CONH-C6H4-CH [CH2CON (CH2CH2NH-) ₂ ] 2; -CONH-C6H4-CH [CH2CON (CH 2 CH ₂ N <) 2] 2; -COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <; groups of formula 187 712 CON (CH ₂ CH ₂ NH-) ₂ -CONI CON (CH ₂ CH ₂ NH-) ₂ CON (CH ₂ CH ₂ N <) ₂ -CONI CON (CH2CH ₂ N <) ₂ 187 712 0 (0 ^ 0Η2θ) 0Η20Η ₂ ΝΗ- IO (CI- ^ CH2O) CK2CH ₂ N < K denotes the radical of the complexing agent, a denotes the number 2-12, x, y, z and, independently of each other, denote the number 1-4, provided that at least two reproductive units are different and that the relationship for the product of multiples is 16 <a x y z w <64, b) at least 16 ions of the element with the ordinal number 20-29, 39,42,44 or 57-83, c) optionally, cations of inorganic or organic bases, amino acids or amino acid amides, and d) egeNtual Amine terminal groups not quoted, characterized by the following characteristics: with the terminal nitrogen atom of the last generation of the reproductive unit W bound radical of the complexing agent K denotes a radical of the general formula ΪΑ r ¹ ooc-r ² hc r ³ N-CH ₂ - CH ₂ -N ch ₂ ch ₂ ch ₂ ch ₂ -CH ₂ - CH ₂ N CHR ² -COOR ¹ CHR ² -COOR ¹ (IA) where R1 Independently of each other denote a hydrogen atom or the equivalent of metal ions with the ordinal number 20-29, 39, 42-44 or 57-83, R represents a hydrogen atom, a methyl or ethyl radical, which is optionally substituted with 1-2 hydroxyl groups or 1 carboxyl group, R3 is a group R ² R ⁴ -CH-CO-NU ⁶ -T R4 represents a straight chain, branched, saturated or unsaturated chain C1-C3o-alkylene. which is optionally separated by 1-10 oxygen atoms, 1 phenylene group, 1 phenylene group, and / or optionally substituted with 1-5 hydroxyl groups, 1-3 carboxyl groups, 1 phenyl group, U ⁶ represents a chain Ci-o-alkylene group containing -CH2-, -CH7NHCO-, -NHCOCH2O-, H4- -NHCOCH2OC _6, -N (CH2C02H) -, -NHCOCH2C6H4-, -NHCSNHC _yellow H4-, -CH2OCiH4- , -CH2CH20-, and / or substituted by -COOH, -CH 2 COOH, preferably a group -CH2- © toCl-a, -C ^ C ^ C ^ -, -CgH4-, -CeHio-, -CH2C6H ₅ -, -CH2NHC0CH2CH (CH2CO2H) -C6H4-, -C ^ NHCOC ^ OC ^ -, -CH2NHCOCH2C6H4-, 187 712 T is the group -CO-a, -NHCO-a or -NHCS-a, aa is the binding site at the terminal nitrogen atom of the last generation of the reproductive unit W, for producing agents for distinguishing benign and malignant tumors in regions of the body without the blood-brain barrier .